**Psoriatic Animal Models Developed for the Study of the Disease**

Sandra Rodríguez‐Martínez, Juan C. Cancino‐Diaz, Isaí Martínez‐Torrez, Sonia M. Pérez‐Tapia and Mario E. Cancino‐Diaz

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68305

#### **Abstract**

contact dermatitis express the skin-selective homing receptor, the cutaneous lympho-

[60] Abernathy-Carver KJ, Sampson HA, Picker LJ, Leung DY. Milk-induced eczema is associated with the expansion of T cells expressing cutaneous lymphocyte antigen. J Clin

[61] Torres MJ, Gonzalez FJ, Corzo JL, Giron MD, Carvajal MJ, Garcia V, Pinedo A, Martinez-Valverde A, Blanca M, Santamaria LF. Circulating CLA+ lymphocytes from children with atopic dermatitis contain an increased percentage of cells bearing staphylococcal-

related T-cell receptor variable segments. Clin Exp Allergy. 1998; 28: 1264-1272.

specific for a skin-tropic virus. J Clin Invest. 2002 110: 537-548. 10.1172/JCI15537

[64] Ogg GS, Rod DP, Romero P, Chen JL, Cerundolo V. High frequency of skin-homing melanocyte-specific cytotoxic T lymphocytes in autoimmune vitilig. J Exp Med. 1998; 188:

[65] Oh CJ, Das KM, Gottlieb AB. Treatment with anti-tumor necrosis factor alpha (TNFalpha) monoclonal antibody dramatically decreases the clinical activity of psoriasis

[66] Leonardi C, Matheson R, Zachariae C, Cameron G, Li L, Edson-Heredia E, Braun D, Banerjee S. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque pso-

[67] Papp KA, Leonardi C, Menter A, Ortonne JP, Krueger JG, Kricorian G, Aras G, Li J, Russell CB, Thompson EH, Baumgartner S. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med. 2012; 366: 1181-1189. 10.1056/NEJMoa1109017 [68] http://www.siliconinvestor.com/readmsgs.aspx?subjectid=24141&msgnum=97&batchsi

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[71] Antoniu SA. Discontinued drugs 2011: pulmonary, allergy, gastrointestinal and arthritis. Expert Opin Investig Drugs. 2012; 21: 1607-1618. 10.1517/13543784.2012.712112

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62: 427-436. S0190-9622(09)00686-0 [pii];10.1016/j.jaad.2009.05.042

[62] Blanca M, Leyva L, Torres MJ, Mayorga C, Cornejo-Garcia J, Antunez-Rodriguez C, Santamaria LF, Juarez C. Memory to the hapten in non-immediate cutaneous allergic reactions to betalactams resides in a lymphocyte subpopulation expressing both CD45RO and CLA markers. Blood Cells Mol Dis. 2003; 31: 75-79. S1079979603000615 [63] Koelle DM, Liu Z, McClurkan CM, Topp MS, Riddell SR, Pamer EG, Johnson AS, Wald A, Corey L. Expression of cutaneous lymphocyte-associated antigen by CD8(+) T cells

cyte-associated antigen. J Exp Med. 1995; 181: 1935-1940.

Invest. 1995. 95: 913-918. 10.1172/JCI117743

74 An Interdisciplinary Approach to Psoriasis

1203-1208.

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Psoriasis is a skin disease mainly developed in humans, although it is also seen in mon‐ keys and dogs. Animal models with psoriasis‐like lesions have been a key factor for its understanding. Xenotransplants of human psoriatic skin in immunodeficient mice were the first approach for the association of immunologic problems with the development of psoriasis and have been also useful for the evaluation on new therapeutic agents. Imiquimod‐induced murine psoriasis is nowadays one of the most used animal models to study this disease, perhaps because healthy wild‐type mice are used, which means that it is an affordable model, easy to generate, and, more importantly, resembles the inflam‐ matory, angiogenic and hyperproliferative characteristics of human psoriasis. Several transgenic (over‐expressing VEGF, Tie2, TGFβ, STAT3, IL‐36, PPARβ/γ) and knockout (lacking IκBα, JunB, IFNR‐2, IL‐36RA, CD18, IKK2) mice have been useful for the associa‐ tion of specific molecules for the development of psoriasis. Other approach has been the use of both transgenic/knockout mice and imiquimod treatment, where the importance of βTrCP, IκBζ, IL‐35 and Tnip1 for the development of psoriasis was found. In this chap‐ ter, some of these animal models are discussed.

**Keywords:** psoriasis, animal models, skin immunology, angiogenesis, keratinocytes

## **1. Introduction**

Psoriasis is a disease that has been accompanying the existence of humans. The ancient Greeks described an illness that seems to be psoriasis, but it could be confused with leprosy or Hansen's disease [1]. Because psoriasis develops naturally in humans but rarely in other species [2, 3], the

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

study of this disease was possible only after progress was made on immunology and on genetic engineering knowledge. Although reports on animals with psoriatic lesions due spontaneous mutations exist, the phenotype does not completely resemble human psoriasis, as occur with the homozygous asebia (Scd1ab/Scd1ab) mutant mice, the Flaky skin mice (Ttcfsn/Ttcfsn) and the spontaneous chronic proliferative dermatitis mutation mice [4, 5]. Now, with the advances on genetic engineering, some transgenic animals and animals with targeted mutations (knockout and knock‐in) have been developed to study psoriasis. In the case of knockout models, the tar‐ geted gene is inactivated and the phenotype is caused by the absence of the targeted gene prod‐ uct. In the case of knock‐in model, the gene is modified through targeted point mutation, with the addition or deletion of a nucleotide, instead of complete disruption of the target gene expression, and the phenotype depends on the expression of modified gene products. Knockout and knock‐ in animals are also developed with the use of tissue specific promoters to eliminate or express the targeted gene, and even more, the expression or suppression of the gene could be controlled by specific promoter regulators, where antibiotics and hormones are frequently used [6].

Another strategy to study psoriasis and other dermatologic illnesses in vitro is the develop‐ ment of 2nd‐ or 3rd‐dimensional cell co‐cultures. These systems have the limitation that so far has not been possible to include all the cellular types that are part of the skin, but have been very useful to evaluate new drugs for treatment [7].

## **2. Immunological factors in psoriasis**

## **2.1. Humanized animal models (xenotransplantation)**

Xenotransplantation was the first approach generated as animal model for the study of pso‐ riasis and for the evaluation of anti‐psoriatic treatments that consists in the transplantation of human skin in the back of inmunodeficient mice. In 1994, the first murine psoriasis model done in mice with severe combined immunodeficiency (SCID) was described. These mice have the so‐called scid mutation that affects the "protein kinase DNA activated catalytic polypeptide" (Prkdc/DNA‐PKcs), causing a defect in the antigen receptor gene rearrangement of lymphocytes, and consequently a SCID of the T‐ and B‐cell systems [8]. In these mice, the psoriatic phenotype is kept for 2 months, enough time for the analysis of the disease. Later, it was demonstrated that mice with non‐psoriatic human skin transplants that received lymphocytes from the psoriatic skin developed psoriasis; these facts demonstrated the importance of the immunologic factor for the development of this disease [9]. Also, the so‐called nude mice are used to study psoriasis; these mice have a mutation in the forkhead box transcription factor N1 that results in defective thymus development, and therefore in lack functional T cells, or nude mice that lack recombinase activating genes 1 (Rag1) and 2 (Rag2) involved in the development of T and B cells.

#### **2.2. Imiquimod‐induced murine psoriasis (IMQ‐Mu‐Pso)**

This transient model of psoriasis‐like disease was developed by Van der Fits et al. [10], using non‐ genetically modified healthy mice daily treated with topic imiquimod or resiquimod (TLR7‐TLR8 ligand) for 6 days. This simple model shows wide characteristics described in the human psoriatic skin lesions, including: activation of pDC, Th17 cells producing IL‐17, IL‐22 and IL‐23, activation of angiogenic process and hyperproliferacion of keratinocytes. IMQ‐Mu‐Pso model is generated due to an acute inflammation in the epidermis induced by imiquimod, hyperactivating the innate immunity and leading the adaptive immunity to produce great amounts of IL‐17. IL‐17, in turn, induces angiogenesis and proliferation of keratinocytes, as biological characteristics of psoriatic lesions. IMQ‐Mu‐Pso also demonstrated that undisrupted molecular and cellular mechanisms are able to break inflammation, as mice used for this model are healthy mice that show the high‐ est production of inflammatory cytokines on the third day of treatment and show the highest development of psoriatic skin on the sixth day, but after this time, the mice are able to revert the inflammatory process as they are not genetically compromised. The short lasting presence of pso‐ riatic lesions is an inconvenience of this model, although it has been widely used to elucidate the pathogenesis of psoriasis, and very interesting data have been published [10].

#### **2.3. Intestinal microbiome affects the induction of psoriasis**

study of this disease was possible only after progress was made on immunology and on genetic engineering knowledge. Although reports on animals with psoriatic lesions due spontaneous mutations exist, the phenotype does not completely resemble human psoriasis, as occur with the homozygous asebia (Scd1ab/Scd1ab) mutant mice, the Flaky skin mice (Ttcfsn/Ttcfsn) and the spontaneous chronic proliferative dermatitis mutation mice [4, 5]. Now, with the advances on genetic engineering, some transgenic animals and animals with targeted mutations (knockout and knock‐in) have been developed to study psoriasis. In the case of knockout models, the tar‐ geted gene is inactivated and the phenotype is caused by the absence of the targeted gene prod‐ uct. In the case of knock‐in model, the gene is modified through targeted point mutation, with the addition or deletion of a nucleotide, instead of complete disruption of the target gene expression, and the phenotype depends on the expression of modified gene products. Knockout and knock‐ in animals are also developed with the use of tissue specific promoters to eliminate or express the targeted gene, and even more, the expression or suppression of the gene could be controlled by

specific promoter regulators, where antibiotics and hormones are frequently used [6].

very useful to evaluate new drugs for treatment [7].

**2.1. Humanized animal models (xenotransplantation)**

**2.2. Imiquimod‐induced murine psoriasis (IMQ‐Mu‐Pso)**

**2. Immunological factors in psoriasis**

76 An Interdisciplinary Approach to Psoriasis

Another strategy to study psoriasis and other dermatologic illnesses in vitro is the develop‐ ment of 2nd‐ or 3rd‐dimensional cell co‐cultures. These systems have the limitation that so far has not been possible to include all the cellular types that are part of the skin, but have been

Xenotransplantation was the first approach generated as animal model for the study of pso‐ riasis and for the evaluation of anti‐psoriatic treatments that consists in the transplantation of human skin in the back of inmunodeficient mice. In 1994, the first murine psoriasis model done in mice with severe combined immunodeficiency (SCID) was described. These mice have the so‐called scid mutation that affects the "protein kinase DNA activated catalytic polypeptide" (Prkdc/DNA‐PKcs), causing a defect in the antigen receptor gene rearrangement of lymphocytes, and consequently a SCID of the T‐ and B‐cell systems [8]. In these mice, the psoriatic phenotype is kept for 2 months, enough time for the analysis of the disease. Later, it was demonstrated that mice with non‐psoriatic human skin transplants that received lymphocytes from the psoriatic skin developed psoriasis; these facts demonstrated the importance of the immunologic factor for the development of this disease [9]. Also, the so‐called nude mice are used to study psoriasis; these mice have a mutation in the forkhead box transcription factor N1 that results in defective thymus development, and therefore in lack functional T cells, or nude mice that lack recombinase

activating genes 1 (Rag1) and 2 (Rag2) involved in the development of T and B cells.

This transient model of psoriasis‐like disease was developed by Van der Fits et al. [10], using non‐ genetically modified healthy mice daily treated with topic imiquimod or resiquimod (TLR7‐TLR8 ligand) for 6 days. This simple model shows wide characteristics described in the human psoriatic The absence of 100% concordance between monozygotic twins suggests a crucial role of environ‐ mental factors for the development of psoriasis, as only 35–75% of monozygotic twins develop psoriasis; alcohol intake and smoking are considered non genetic factors that predispose indi‐ viduals to develop psoriasis [11]. Intestinal microbiota has an important effect on the develop‐ ment and function of the immune system, for instance, a specific subset of microbiota has been shown to play roles in the development of Th17, meanwhile other subset favors the develop‐ ment of Treg cells [12]. Another study showed that microbiota from skin of psoriatic patients is different from healthy subjects; *Proteobacteria* were present at significantly higher levels in the psoriatic skin compared to limb skin used as control (52 vs. 32%, p = 0.0113), and in the same study, both *Staphylococci* and *Propionibacteria* were significantly lower in psoriasis versus control (p = 0.051, 0.046, respectively) [13]. In 2015, Zanvit et al. demonstrated that psoriasis is medi‐ ated by the early interaction between certain subset of bacterial microbiota and cells of immune system [14]. They treated 4‐week‐old mice with oral antibiotics (vancomycin and polymyxin B) showing a decrease in the severity of psoriasis compared to mice without antibiotics using the IMQ‐Mu‐Pso model. IL‐17+ and IL‐22+ T cells were significantly decreased in skin and gut in the antibiotic‐treated mice; however, the Foxp3+ Treg cells were significantly increased in the skin of these mice. In contrast, when neonatal mice received the antibiotic treatment and the psoriasis was induced with imiquimod as 4‐week old, they observed an increase in the severity of disease compared to mice without antibiotic treatment evidenced by the presence of immunological cells infiltration and by the increase of thickness in dermis; besides they did not find augment of IL‐17+ cells, but significant increase of IL‐22+ cells. The intestinal microbiota was also consider‐ ably different between mice treated with antibiotics as adults from those treated as neonates [14]. These results settle that among the factors that predispose to psoriasis is intestinal microbiota that depends on breast feed as neonates, type of food intake, but also on the use of antibiotics.

#### **2.4. Disruption of NFκB and AP‐1 to generate psoriasis in animal models**

Innate immunity in skin is mediated by the activation of membrane receptors expressed on dendritic cells, Langerhans cells and macrophages activated by pathogens‐ or damage‐molec‐ ular patterns (PAMP or DAMP). After ligand‐receptor interaction, molecular signaling events occur into the cell leading to the activation of transcription factors, such as NFκB and AP‐1 that translocate into the nucleus for the expression of cytokines and antimicrobial peptides [15]. The malfunctioning in the regulation of the activity of these transcription factors could lead to the development of psoriatic lesions, as we next describe.

In unstimulated cells, NFκB dimers are sequestered in the cytoplasm by a family of inhibitors called IκB (Inhibitor of κB), and the IκB proteins mask the nuclear localization signals (NLS) of NFκB proteins and keep them sequestered in an inactive state in the cytoplasm. Activation of NFκB is initiated by the signal‐induced degradation of IκB proteins; this occurs primarily by the activation of a kinase called IκB kinase (IKK). When activated by PAMPs or DAMPs, IKK phosphorylates two serine residues located in IκBα's regulatory domain, and then IκBα is ubiquitinated and degraded by the proteasome. With the degradation of IκBα, NFκB dimer is freed to enter into the nucleus to initiate the expression of specific genes that have DNA‐ binding sites for NFκB at their promoter site. The transcription of the targeted genes initiates a physiological response, for example, inflammation, cell survival and cellular proliferation. In fact, NFκB turns on the expression of its own repressor, IκBα. The newly synthesized IκBα then inhibits NFκB activity controlling the function of NFκB in an oscillatory way [15].

In IMQ‐Mu‐Pso, the severity of psoriatic lesions has been associated with a reduced pres‐ ence of IκBα due over‐degradation and in consequence with an enhanced NFκB activation. IκBα knockout mice developed psoriasis and died within the 7th–10th day after birth. The histological analysis showed myelopoietic tissues enlarged and diffusely distributed, and also alterations in the liver with enhanced splenic extramedullary hematopoiesiswith increased presence of monocytes/macrophages was seen [16].

"β‐transducin repeat‐containing protein" (β‐TrCP) serves as substrate recognition component of E3 ubiquitin ligase that control the stability of important regulators of signal transduction, including IκBα. Mice with down‐regulation of βTrCP ameliorate IMQ‐Mu‐Pso skin lesions, as IκBα does not degrade, keeping NFκB into the cytoplasm. This interesting finding suggests that βTrCP could be a novel target for developing agents to treat psoriasis, since it is involved in the NFκB signaling to regulate inflammation [17].

IκBζ is another molecule that interacts with NFκB, but inside the nucleus. This molecule has been recently identified as a key regulator in the development of psoriasis [18]. IκBζ is increased in psoriatic skin compared to non‐psoriatic skin from the same patient. Some stud‐ ies suggest that IκBζ associates with NFκB p50 subunit and binds to specific IκBζ response elements located in the promoter region of targeted genes consisting of NFκB‐ and C/EBP (CCAAT/enhancer‐binding protein)‐binding sites and exerts its transcription‐enhancing activ‐ ity on secondary response genes primarily by chromatin remodeling [19]. IκBζ is expressed in human keratinocytes induced with IL‐17 and is a direct transcriptional activator of TNFα/ IL‐17‐inducible psoriasis‐associated proteins such as IL‐8, IL‐17C, IL‐17A22, IL‐19, IL23, IL22, CCL20 and hBD220. Interestingly, in imiquimod‐treated IκBζ‐deficient mice, psoriatic skin is not observed, and the molecules induced by TNFα/IL‐17 are significantly down‐expressed [20].

The dysfunctional activity of other transcription factors, for instance, AP‐1 and STAT3, also contributes to skin inflammation development [21]. Mice with deficient expression of JunB and c‐Jun, and mice with over‐expression of FOS, generate a phenotype resembling the histological characteristics of psoriasis, including the production pro‐inflammatory cyto‐ kines. Besides, JunBexpression is reduced in epidermal keratinocytes of psoriatic patients in comparison with cells from healthy subjects [21]. Moreover, STAT3 transgenic mice and SOCS3 knockout mice (the negative regulator of STAT3) have constitutive activation of STAT3 and both develop murine IL‐6‐driven psoriasis [22, 23].

#### **2.5. The role of cytokines in psoriasis**

occur into the cell leading to the activation of transcription factors, such as NFκB and AP‐1 that translocate into the nucleus for the expression of cytokines and antimicrobial peptides [15]. The malfunctioning in the regulation of the activity of these transcription factors could lead to the

In unstimulated cells, NFκB dimers are sequestered in the cytoplasm by a family of inhibitors called IκB (Inhibitor of κB), and the IκB proteins mask the nuclear localization signals (NLS) of NFκB proteins and keep them sequestered in an inactive state in the cytoplasm. Activation of NFκB is initiated by the signal‐induced degradation of IκB proteins; this occurs primarily by the activation of a kinase called IκB kinase (IKK). When activated by PAMPs or DAMPs, IKK phosphorylates two serine residues located in IκBα's regulatory domain, and then IκBα is ubiquitinated and degraded by the proteasome. With the degradation of IκBα, NFκB dimer is freed to enter into the nucleus to initiate the expression of specific genes that have DNA‐ binding sites for NFκB at their promoter site. The transcription of the targeted genes initiates a physiological response, for example, inflammation, cell survival and cellular proliferation. In fact, NFκB turns on the expression of its own repressor, IκBα. The newly synthesized IκBα then inhibits NFκB activity controlling the function of NFκB in an oscillatory way [15].

In IMQ‐Mu‐Pso, the severity of psoriatic lesions has been associated with a reduced pres‐ ence of IκBα due over‐degradation and in consequence with an enhanced NFκB activation. IκBα knockout mice developed psoriasis and died within the 7th–10th day after birth. The histological analysis showed myelopoietic tissues enlarged and diffusely distributed, and also alterations in the liver with enhanced splenic extramedullary hematopoiesiswith increased

"β‐transducin repeat‐containing protein" (β‐TrCP) serves as substrate recognition component of E3 ubiquitin ligase that control the stability of important regulators of signal transduction, including IκBα. Mice with down‐regulation of βTrCP ameliorate IMQ‐Mu‐Pso skin lesions, as IκBα does not degrade, keeping NFκB into the cytoplasm. This interesting finding suggests that βTrCP could be a novel target for developing agents to treat psoriasis, since it is involved

IκBζ is another molecule that interacts with NFκB, but inside the nucleus. This molecule has been recently identified as a key regulator in the development of psoriasis [18]. IκBζ is increased in psoriatic skin compared to non‐psoriatic skin from the same patient. Some stud‐ ies suggest that IκBζ associates with NFκB p50 subunit and binds to specific IκBζ response elements located in the promoter region of targeted genes consisting of NFκB‐ and C/EBP (CCAAT/enhancer‐binding protein)‐binding sites and exerts its transcription‐enhancing activ‐ ity on secondary response genes primarily by chromatin remodeling [19]. IκBζ is expressed in human keratinocytes induced with IL‐17 and is a direct transcriptional activator of TNFα/ IL‐17‐inducible psoriasis‐associated proteins such as IL‐8, IL‐17C, IL‐17A22, IL‐19, IL23, IL22, CCL20 and hBD220. Interestingly, in imiquimod‐treated IκBζ‐deficient mice, psoriatic skin is not observed, and the molecules induced by TNFα/IL‐17 are significantly down‐expressed [20]. The dysfunctional activity of other transcription factors, for instance, AP‐1 and STAT3, also contributes to skin inflammation development [21]. Mice with deficient expression of JunB and c‐Jun, and mice with over‐expression of FOS, generate a phenotype resembling the

development of psoriatic lesions, as we next describe.

78 An Interdisciplinary Approach to Psoriasis

presence of monocytes/macrophages was seen [16].

in the NFκB signaling to regulate inflammation [17].

Other sort of psoriatic animal models includes those where cytokines and cells of immune system are involved. The importance of type I interferons in the psoriasis was demonstrated in "IFN regulatory factor‐2" (IFNR‐2)‐deficient mice, a transcriptional repressor for IFN‐αβ signaling. These mice developed skin lesions similar to human psoriasis [24], in fact, type I interferons promote the activation of dermal dendritic cells (dDCs) [25].

Another cytokine with importance for the development of psoriasis is IL‐36, an IL‐1 family sub‐member. The over‐expression of IL‐36α in transgenic murine (K14/IL‐36) keratinocytes promotes acanthosis, hyperkeratosis, cells infiltration and increased expression of cytokines and chemokines [26]. The deficiency of IL‐36RA (the natural antagonist of IL‐36) in IL‐36α (K14/IL‐36, IL‐36RA−/−)‐transgenic mice exacerbates the severity of psoriasis; histological analysis reveals intracorneal and intraepithelial pustules, parakeratotic and orthokeratotic hyperkeratosis, dilated superficial dermal blood vessels, and dermal inflammatory infiltrate. Additionally, mice deficient to IL‐36 or in its receptor IL‐36R are protected from IMQ‐Mu‐Pso [26]. In turn, IL‐1β, TNFα, and IL‐36 activate dDC and induce the production of IL‐23, nec‐ essary for naive T cells to polarize to Th17, suggesting that IL‐23 could be the link between the innate and adaptive immune response that occur in psoriasis [27]. In fact, it is possible to obtain psoriasiform skin in wild‐type mice with nothing more but the inoculation of recombi‐ nant IL‐23 or IL‐17 [28]. In contrast, IL‐35 has a potent immunosuppressive effect on HaCaT keratinocytes treated with TNF‐α and IL‐17 suppressing the expression of IL‐6, CXCL8, and S100A7 [28]. In IMQ‐Mu‐Pso and K14‐VEGF transgenic mice model, IL‐35 reduced M1 mac‐ rophages (F4/80+CD80+), whereas anti‐inflammatory M2 macrophages (F4/80+CD206+) were increased in the spleen and ear. IL‐10–secreting CD4+, FoxP3+, CD25+ T cells were increased in those tissues, although IL‐10–secreting CD25‐T cells were also increased [29]. These results suggest that IL‐35 treatment for psoriasis increases M2 macrophages as well as IL‐10 produc‐ tion but suppresses Th17 cells development, consistent with the effect of IL‐35 on Treg expan‐ sion, although not all IL‐10 was secreted by Treg cells.

## **2.6. Cellular immunology in psoriasis**

The insufficient regulation of specific cellular immune response is also involved in the devel‐ opment of psoriasis [30]. In normal conditions, Treg cells regulate the activity of auto‐reactive Th1 and Th17 cells, but in psoriasis Treg cells might not be functional, as was evidenced in the CD18hypo mouse model [31]. Homozygous PL/J CD18 hypomorphic (CD18hypo)‐mice developed spontaneously psoriasis‐like skin in 12‐ to 14‐week‐old mice. CD18 is a molecule that together with CD11a constitutes an adhesion molecule of the β2 integrin family, impor‐ tant for the complete function of Treg cells. It has been suggested that CD18hypo mice induce psoriasis because CD18‐low expressing Treg cells, or with a not fully active molecule, cannot regulate the activity of auto‐reactive Th1 and Th17 cells, since these mice improve when Treg cells from normal mice are transferred [32]. In CD18hypo mice, psoriatic lesions meliorate when macrophages are eliminated by the use of clodronate liposomes in the skin [33]. These results show the importance of Treg cell and macrophages in the evolution of psoriasis.

## **2.7. Implantable synthetic cytokine‐converter cells model**

Schukur et al. [34] designed the so‐called implantable synthetic cytokine converter cells system based on the observation that psoriatic patients have high concentrations of TNFα and IL‐22, and on the fact that IL‐4 and IL‐10 cytokines have an important anti‐psoriatic effect. Considering the previous, they generated by genetic engineering human cells to react to high concentra‐ tions of TNFα and IL‐22; these cells would be implanted to psoriatic patients and activated by TNFα and IL‐22 from a psoriatic flare, and as a result, they would produce therapeutic doses of IL‐4 and IL‐10 to control inflammation. To achieve the goal, HEK‐293T cells were co‐trans‐ fected with the plasmids pNFκB‐hIL‐22RA‐pA, phCMV‐hSTAT3‐pA, pSTAT3‐mIL‐4‐pA and pSTAT3‐mIL‐10‐pA. The authors first confirmed that co‐transfected cells produced important levels of IL‐4 and IL‐10 when stimulated with TNFα and IL‐22 in vitro [34]. TNFα activated the production of IL‐22 receptor, and in turn IL‐22 activated STAT3 signaling to induce the pro‐ duction of IL‐4 and IL‐10, to generate an anti‐inflammatory environment. When co‐transfected HEK‐293T cells were intraperitoneally implanted into mice with IMQ‐Mu‐Pso the cytokines associated with the pathogenesis of psoriasis, such as IL‐17, IFNα and C‐X‐C motif chemokine 9 (CXCL9), decreased substantially and a considerable increase in the production of the anti‐ inflammatory cytokines IL‐4 and IL‐10 was observed on day 5. Only the skin of animals with implanted co‐transfected cells containing the antipsoriatic cytokine converter showed reduced skin lesions, evidenced by the reduction of erythema, scaling, and thickening. This is an inter‐ esting approach to treat psoriasis, although the complexity relies on the requirement to co‐ transfect cells from every single patient to avoid transplant rejection. Meanwhile, this system was also evaluated in vitro using blood from psoriatic patients and from healthy individuals, and interestingly only in blood from psoriatic patients increased levels of anti‐inflammatory cytokines were detected [34].

## **3. Angiogenic factor in psoriasis**

The altered function of angiogenic molecules also produces psoriasis. "Vascular endothelial growth factor" (VEGF)‐transgenic mice [35], "endothelial specific receptor tyrosine kinase" (K5‐Tie2)‐transgenic mice [36], and "transforming growth factor beta 1" (K5‐TGFβ1)‐trans‐ genic mice [37] are psoriasis animal models that highlight the importance of angiogenesis in this pathology. VEGF is a crucial factor that mediates the angiogenesis of blood vessels and is highly expressed in the psoriatic skin lesions. VEGF induces microvascular alterations in the dermal papillae, which facilitate the development and persistence of the psoriatic lesions [35]. Moreover, the increased vasculature and permeability provide nutrition to the hyperp‐ roliferating keratinocytes and promote the migration of inflammatory cells. The 6‐month‐ old K14‐VEGF mice develop psoriasis, but if these mice are treated with imiquimod at 8‐week old, the skin thickens, chemokines CXCL‐9/10, CCL‐20 and CCR6 increase, cytokines IL‐23, IL‐17, TNFα, and (IFN)‐γ rise, and the cells CD11c+ DCs, Th17, Th1, γδ‐T increase. In wild‐type mice IMQ‐Mu‐Pso skin lesions last until day 7 of treatment, but in K14‐VEGF mice treated with imiquimod, all the parameters described above are stable until day 14 [38]. This combined model IMQ‐K14‐VEGF is more appropriate for long‐term studies compared to IMQ‐Mu‐Pso model, which is only an acute chemical‐stimulated model.

Tie2 is the angiopoietin receptor that together with VEGF is essential for proliferation, mat‐ uration and for the maintenance of blood vessels. Hyperproliferation of keratinocytes and abundance of immunological cells infiltration, including Th17 cells, are detected in psoriatic skin. The over‐expression of VEGF is promoted by TGFβ but also can be regulated by HIF‐1α, as it is over‐expressed in the psoriatic skin [36].

## **4. The role of keratinocytes in psoriasis**

## **4.1. PPAR β/δ**

regulate the activity of auto‐reactive Th1 and Th17 cells, since these mice improve when Treg cells from normal mice are transferred [32]. In CD18hypo mice, psoriatic lesions meliorate when macrophages are eliminated by the use of clodronate liposomes in the skin [33]. These results show the importance of Treg cell and macrophages in the evolution of psoriasis.

Schukur et al. [34] designed the so‐called implantable synthetic cytokine converter cells system based on the observation that psoriatic patients have high concentrations of TNFα and IL‐22, and on the fact that IL‐4 and IL‐10 cytokines have an important anti‐psoriatic effect. Considering the previous, they generated by genetic engineering human cells to react to high concentra‐ tions of TNFα and IL‐22; these cells would be implanted to psoriatic patients and activated by TNFα and IL‐22 from a psoriatic flare, and as a result, they would produce therapeutic doses of IL‐4 and IL‐10 to control inflammation. To achieve the goal, HEK‐293T cells were co‐trans‐ fected with the plasmids pNFκB‐hIL‐22RA‐pA, phCMV‐hSTAT3‐pA, pSTAT3‐mIL‐4‐pA and pSTAT3‐mIL‐10‐pA. The authors first confirmed that co‐transfected cells produced important levels of IL‐4 and IL‐10 when stimulated with TNFα and IL‐22 in vitro [34]. TNFα activated the production of IL‐22 receptor, and in turn IL‐22 activated STAT3 signaling to induce the pro‐ duction of IL‐4 and IL‐10, to generate an anti‐inflammatory environment. When co‐transfected HEK‐293T cells were intraperitoneally implanted into mice with IMQ‐Mu‐Pso the cytokines associated with the pathogenesis of psoriasis, such as IL‐17, IFNα and C‐X‐C motif chemokine 9 (CXCL9), decreased substantially and a considerable increase in the production of the anti‐ inflammatory cytokines IL‐4 and IL‐10 was observed on day 5. Only the skin of animals with implanted co‐transfected cells containing the antipsoriatic cytokine converter showed reduced skin lesions, evidenced by the reduction of erythema, scaling, and thickening. This is an inter‐ esting approach to treat psoriasis, although the complexity relies on the requirement to co‐ transfect cells from every single patient to avoid transplant rejection. Meanwhile, this system was also evaluated in vitro using blood from psoriatic patients and from healthy individuals, and interestingly only in blood from psoriatic patients increased levels of anti‐inflammatory

The altered function of angiogenic molecules also produces psoriasis. "Vascular endothelial growth factor" (VEGF)‐transgenic mice [35], "endothelial specific receptor tyrosine kinase" (K5‐Tie2)‐transgenic mice [36], and "transforming growth factor beta 1" (K5‐TGFβ1)‐trans‐ genic mice [37] are psoriasis animal models that highlight the importance of angiogenesis in this pathology. VEGF is a crucial factor that mediates the angiogenesis of blood vessels and is highly expressed in the psoriatic skin lesions. VEGF induces microvascular alterations in the dermal papillae, which facilitate the development and persistence of the psoriatic lesions [35]. Moreover, the increased vasculature and permeability provide nutrition to the hyperp‐ roliferating keratinocytes and promote the migration of inflammatory cells. The 6‐month‐ old

**2.7. Implantable synthetic cytokine‐converter cells model**

cytokines were detected [34].

80 An Interdisciplinary Approach to Psoriasis

**3. Angiogenic factor in psoriasis**

The "peroxisome proliferator‐activated receptor" (PPAR β/δ) transgenic mice, and the human keratinocytes autocrine growth factor (amphiregulin) transgenic mice [39, 40] both resemble psoriasis because they participate in the proliferation and differentiation of keratinocytes [41]. PPAR β/δ receptor is induced by TNFα, contributes to STAT3 phosphorylation, blocks apop‐ tosis in keratinocytes, induces angiogenesis, and is up‐regulated in human psoriatic skin [42]. In fact, PPAR β/δ directly induces the differentiation of keratinocytes, and in the transgenic mouse model, a light augment of Th17 is observed [43].

## **4.2. NFκB inhibits proliferation in keratinocytes**

Genome‐wide association studies suggest a link between psoriasis and the NFκB pathway, and this proposal has been supported by mouse models. Evidence gathered from diverse studies has shown that NFκB has a growth inhibitory function in the skin. Mice with epi‐ dermis‐specific deletion of IKK2 (which mediates canonical NFκB activation) develop severe inflammatory skin disease that is mediated by TNFα, suggesting the critical function of IKK2‐mediated NFκB activity in epidermal keratinocytes to regulate mechanisms that main‐ tain the immune homeostasis of the skin [44].

Grinberg‐Bleyer, et al. [45] described a murine psoriasis model that lacks the expression of p65 and c‐Rel in epidermal cells. After birth, these mice developed severe psoriasis; early lesions were well‐demarcated, scattered and rigid, with scaly plaques without edematous or exudative reaction aspect. H&E staining revealed epidermal thickening, hyperkeratosis and focal parakeratosis, as well as mononuclear infiltrates in the epidermis, which are features of psoriatic lesions. In this model, psoriatic lesions were resolved 30 days after birth by Treg cells effect, but when these cells were eliminated by the use of anti‐CD25 antibodies, the deficient mice showed a worsened pathology and the psoriatic lesions were reversed with anti‐TNFα treatment [45]. Also RelA has a growth‐inhibitory role in keratinocytes and prevents their differentiation [46]. Together, these results indicate that activation of canonical NFκB path‐ way in keratinocytes is required for their optimal differentiation and for the maintenance of immune homeostasis in the skin.

## **4.3. Prokineticin 2**

Prokineticin2 (PK2), also named Bv8, is a small 8 KDa protein found in serum and dermis of pso‐ riatic patients. PK2 participates in numerous important physiological processes including inflam‐ mation, neurogenesis, tissue development, angiogenesis, and even nociception [47, 48]. This peptide is mainly expressed in brain but can also be found in skin, bone marrow, lymphoid organs, granulocytes, dendritic cells and macrophages [49]. He et al. [50] found that bacterial products, including LPS and DNA, promoted in macrophages the production of PK2 and inflamma‐ tory factors, suggesting that infection is a primary inducer of PK2. The authors demonstrated that in macrophages PK2 induced high production of IL‐1β, and in keratinocytes and fibroblast co‐cultures PK2 induced IL‐6, IL‐8 and GM‐SCF. In vivo PK2 promoted the differentiation of fibroblast and keratinocytes [51]. Besides, when PK2 was over‐expressed in psoriasis‐K14‐VEGF transgenic mouse model, psoriatic lesions were gradually aggravated, as evaluated by increase of redness, swelling, weight, thickness, scaly epidermis, keratinocyte hyper‐proliferation, and increase of IL‐1β, TNFα, IFNγ, IL‐12, IL‐22, IL‐23, IL‐17 in the ear; moreover, increase of lymph node weight was also seen. On the contrary, in psoriatic‐K14‐VEGF transgenic mouse model with PK2 down‐regulated, the psoriatic lesions were abrogated [50]. The results suggest that PK2 aggravates psoriasis by the promotion of keratinocytes and fibroblasts proliferation, inflamma‐ tion, and angiogenesis.

#### **4.4. Tnip1**

The big dilemma about psoriasis is whether the root of the problem falls on keratinocytes or on immunological cells dysfunction. It has been well described that IL‐23‐producing myeloid cells and IL‐17–producing T cells are abundant in psoriatic skin, and that IL‐23 and IL‐17 induce in keratinocytes and fibroblasts high production of chemokines, which in turn, recruit even more immunological cells creating a feedback loop that worsens the disease. In keratinocytes and immunological cells, "TNFAIP3‐inter‐acting protein 1" (Tnip1) down‐ regulates the chemokines production induced by IL‐17 [50]. Ippagunta et al. [52], using the IMQ‐Mu‐Pso model under the Tnip‐keratinocyte‐specific‐deletion mice (Tnip1flox/flox K14‐ Cre), found that keratinocytes contribute intrinsically to psoriasis because when keratino‐ cytes lost Tnip1 function they could not control the production of chemokines induced by IL‐17. Tnip1flox/ floxK14‐Cre mice developed severe psoriasis when low doses of imiquimod were used, even at concentrations on which WT mice do not develop psoriasis. Interestingly, when bone marrow cells from Tnip1‐/‐ mice were transferred to WT mice and treated with low doses of imiquimod, they did not developed psoriasis, confirming that the lack of func‐ tion of Tnip1 in keratinocytes and fibroblast, but not in hematopoietic lineage cells, generate psoriasis [52]. With these results, the authors provide evidence that specifically skin‐resident keratinocytes contribute causally to psoriasis.

## **5. In vitro models for the study of psoriasis**

As we previously mentioned, animal models have been very useful to dissect the molecular and cellular mechanisms for psoriasis development. These models have been also advanta‐ geous to evaluate new pharmaceuticals, nevertheless the physiology, anatomy and molecular differences between animal models and humans cause that only around 10% of new treat‐ ments assayed on phase I, be really useful in humans [53]. Although humanized models have also been developed, immunodeficient animals are most commonly used. Alternative meth‐ ods have been developed to analyze the effect of new anti‐psoriatic drugs; 2D, 2D+membrane, and 3D cell cultures have been designed [54]. 2D model consists of primary explants of kera‐ tinocytes or fibroblasts from psoriatic patients cultured over extracellular matrix proteins to evaluate cellular proliferation, cellular differentiation and cytokines production [55]. In the 2D+membrane model, two cell types are co‐cultured separated by a synthetic membrane to evaluate the interconnection between two cell types in the pathology [56]. 3D cultures, also known as organotypic culture system (OCS), allow the growth of complex biological systems in vitro in a way that resembles part of their normal physiology and function. OCSs are pow‐ erful as experimental platforms in preclinical dermatological research, helping to validate mechanisms of diseases and to test the therapeutic potential of candidate drugs [57]. The new generation of 3D cultures connected to biosensors or chips allows real‐time monitoring of biological parameters such as loss of water and electrophysiologic parameters [58].

## **6. Conclusion**

mice showed a worsened pathology and the psoriatic lesions were reversed with anti‐TNFα treatment [45]. Also RelA has a growth‐inhibitory role in keratinocytes and prevents their differentiation [46]. Together, these results indicate that activation of canonical NFκB path‐ way in keratinocytes is required for their optimal differentiation and for the maintenance of

Prokineticin2 (PK2), also named Bv8, is a small 8 KDa protein found in serum and dermis of pso‐ riatic patients. PK2 participates in numerous important physiological processes including inflam‐ mation, neurogenesis, tissue development, angiogenesis, and even nociception [47, 48]. This peptide is mainly expressed in brain but can also be found in skin, bone marrow, lymphoid organs, granulocytes, dendritic cells and macrophages [49]. He et al. [50] found that bacterial products, including LPS and DNA, promoted in macrophages the production of PK2 and inflamma‐ tory factors, suggesting that infection is a primary inducer of PK2. The authors demonstrated that in macrophages PK2 induced high production of IL‐1β, and in keratinocytes and fibroblast co‐cultures PK2 induced IL‐6, IL‐8 and GM‐SCF. In vivo PK2 promoted the differentiation of fibroblast and keratinocytes [51]. Besides, when PK2 was over‐expressed in psoriasis‐K14‐VEGF transgenic mouse model, psoriatic lesions were gradually aggravated, as evaluated by increase of redness, swelling, weight, thickness, scaly epidermis, keratinocyte hyper‐proliferation, and increase of IL‐1β, TNFα, IFNγ, IL‐12, IL‐22, IL‐23, IL‐17 in the ear; moreover, increase of lymph node weight was also seen. On the contrary, in psoriatic‐K14‐VEGF transgenic mouse model with PK2 down‐regulated, the psoriatic lesions were abrogated [50]. The results suggest that PK2 aggravates psoriasis by the promotion of keratinocytes and fibroblasts proliferation, inflamma‐

The big dilemma about psoriasis is whether the root of the problem falls on keratinocytes or on immunological cells dysfunction. It has been well described that IL‐23‐producing myeloid cells and IL‐17–producing T cells are abundant in psoriatic skin, and that IL‐23 and IL‐17 induce in keratinocytes and fibroblasts high production of chemokines, which in turn, recruit even more immunological cells creating a feedback loop that worsens the disease. In keratinocytes and immunological cells, "TNFAIP3‐inter‐acting protein 1" (Tnip1) down‐ regulates the chemokines production induced by IL‐17 [50]. Ippagunta et al. [52], using the IMQ‐Mu‐Pso model under the Tnip‐keratinocyte‐specific‐deletion mice (Tnip1flox/flox K14‐ Cre), found that keratinocytes contribute intrinsically to psoriasis because when keratino‐ cytes lost Tnip1 function they could not control the production of chemokines induced by

were used, even at concentrations on which WT mice do not develop psoriasis. Interestingly, when bone marrow cells from Tnip1‐/‐ mice were transferred to WT mice and treated with low doses of imiquimod, they did not developed psoriasis, confirming that the lack of func‐ tion of Tnip1 in keratinocytes and fibroblast, but not in hematopoietic lineage cells, generate

floxK14‐Cre mice developed severe psoriasis when low doses of imiquimod

immune homeostasis in the skin.

82 An Interdisciplinary Approach to Psoriasis

**4.3. Prokineticin 2**

tion, and angiogenesis.

**4.4. Tnip1**

IL‐17. Tnip1flox/

The actual hypothesis about the cellular and molecular mechanisms that lead to the develop‐ ment of psoriatic lesions has been established by the use of animal models. The use of xeno‐ transplants confirmed the important role of immunology in this disease. The studies done in genetically modified mice that overproduce (transgenic) or lack (knockout) certain proteins reveal specific protagonists of innate or adaptive immunity, angiogenesis or proliferation for the development of psoriasis.

In **Figure 1**, we represent a developing inflammation mechanism generated in the skin of healthy individuals denoted as a brown cogwheel system, where a trigger induces the innate and adaptive immune response, and in turn angiogenesis and keratinocytes proliferation are activated. Every cog represents one participant in inflammation: cell (DCs, macrophages, iLC IL‐17+, Th1, Th17, keratinocytes, between others) or molecule (TLRs, NFκB, βTrCP, IκBζ, Stat3, TNFα, IFNα, IL‐12, IL‐36, IL‐23, Th1, IL‐6, Th17, IL‐17, CCR6, VEGF, Tie2 TGFβ1, PPARαβ, PK2, between others). The red arrows indicate the movement of the cogwheels for the progression of inflammation. In healthy people, the inflammation is controlled by

**Figure 1.** Inflammatory process. The developing inflammation mechanism generated in the skin is represented in this cogwheel system, where innate immune response, adaptive immune response, angiogenesis and cellular proliferation are represented in independent but interconnected cogwheels. Brown cogwheels represent inflammatory mechanisms moving in a pro‐inflammatory sense (red arrows), where each cog represents one participant in inflammation (cell or molecule). Gray cogwheels represent the anti‐inflammatory mechanism spinning the wheels in the opposite direction (blue arrows) to regulate inflammation. The "ghost" cogs (discontinuous lines) represent dysfunctional cells or molecules that disrupt effectiveness in the control of inflammation, favoring the development of psoriasis. Some antibodies interfere with the spinning of pro‐inflammatory cogwheels, representing therapies with antibodies developed to control psoriasis. Question marks represent molecules to be discovered.

the activation of anti‐inflammatory process after damage reparation. The cells (Treg and M2 macrophages) and molecules (IκBα, JunB, SOCS‐3, IFNR‐2, IL‐36RA, IL‐4, IL‐10, IL‐35, CD18, VHL, Tnip‐1, between others) involved in the anti‐inflammatory process are repre‐ sented in the gray cogwheels. The blue arrows indicate the movement of the cogwheels for the progression of anti‐inflammation. The "ghost" cogs (discontinuous lines) represent those dysfunctional molecules or cells that disrupt effectiveness in the control of inflammation, favoring the development of psoriasis.

Based on all the facts discussed in this chapter, we can conclude that psoriasis occurs in indi‐ viduals with the anti‐inflammatory regulation disrupted in immunological but also in non‐ immunological skin‐resident cells.

## **Acknowledgements**

This work was supported by a grant from the "SIP‐IPN" (Num. SIP20161111). SRM, JCCD, SMPT and MECD belong to COFAA, EDI‐IPN and SNI fellowships. IMT belongs to BEIFI and CONACyT fellowships.

## **Author details**

Sandra Rodríguez‐Martínez1 , Juan C. Cancino‐Diaz<sup>2</sup> , Isaí Martínez‐Torrez1 , Sonia M. Pérez‐Tapia1,3 and Mario E. Cancino‐Diaz1 \*

\*Address all correspondence to: mecancinod@gmail.com

1 Immunology Department, Escuela Nacional de Ciencias Biológicas‐IPN, Mexico City, Mexico

2 Microbiology Department, Escuela Nacional de Ciencias Biológicas‐IPN, Mexico City, Mexico

3 UDIBI, Escuela Nacional de Ciencias Biológicas‐IPN, Mexico City, Mexico

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**Figure 1.** Inflammatory process. The developing inflammation mechanism generated in the skin is represented in this cogwheel system, where innate immune response, adaptive immune response, angiogenesis and cellular proliferation are represented in independent but interconnected cogwheels. Brown cogwheels represent inflammatory mechanisms moving in a pro‐inflammatory sense (red arrows), where each cog represents one participant in inflammation (cell or molecule). Gray cogwheels represent the anti‐inflammatory mechanism spinning the wheels in the opposite direction (blue arrows) to regulate inflammation. The "ghost" cogs (discontinuous lines) represent dysfunctional cells or molecules that disrupt effectiveness in the control of inflammation, favoring the development of psoriasis. Some antibodies interfere with the spinning of pro‐inflammatory cogwheels, representing therapies with antibodies developed to control

Based on all the facts discussed in this chapter, we can conclude that psoriasis occurs in indi‐ viduals with the anti‐inflammatory regulation disrupted in immunological but also in non‐

This work was supported by a grant from the "SIP‐IPN" (Num. SIP20161111). SRM, JCCD, SMPT and MECD belong to COFAA, EDI‐IPN and SNI fellowships. IMT belongs to BEIFI and

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84 An Interdisciplinary Approach to Psoriasis

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**Immune System Links Psoriasis-Mediated Inflammation to Cardiovascular Diseases via Traditional and Non-Traditional Cardiovascular Risk Factors**

Rodolfo A. Kölliker Frers, Matilde Otero-Losada, Eduardo Kersberg, Vanesa Cosentino and Francisco Capani

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68559

#### **Abstract**

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90 An Interdisciplinary Approach to Psoriasis

**Background**. Cutaneous psoriasis and psoriatic arthritis increase the risk of cardiovascular diseases though the reasons are not clear. Here we discuss the role of the immune system in atherosclerosis and of the proinflammatory status in psoriasis and psoriatic arthritis diseases.

**Methods**. We performed a Pubmed query covering publications within the last ten years including epidemiological studies, cross-sectional case-control studies, and reviews. Articles were selected according critical associations using arthritis, immune-mediated inflammatory diseases, and psoriasis as key fields. These were crossed and combined with atherogenesis, endothelial dysfunction, intima-media thickness, subclinical atherosclerosis, plaque, thrombosis, thrombus, fibrinolysis, coagulation, and reactive oxygen species, all closely related to cardiovascular diseases. Both types of disease selected terms were separately combined with cardiovascular risk factors both non-traditional (innate and adaptive pro- and anti-inflammatory immune molecules and cells), and traditional (metabolic conditions and related molecules).

**Results and conclusions**. Immune-activated crossroads came out as the main contributors to proatherogenic inflammation in psoriasis and psoriatic arthritis disease. Traditional and non-traditional cardiovascular risk factors´ interactions result from an active cross-talk between proatherogenic mediators derived from metabolic, vascular and autoimmune joint and skin inflammation in target tissues. Consistently, psoriasis and psoriatic arthritis diseases offer an invaluable scenario to deepen our knowledge on atherosclerotic cardiovascular disease.

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Keywords:** psoriasis, psoriatic arthritis, inflammation, immune system, cardiovascular risk factors

## **1. Introduction**

Traditional cardiovascular risk factors like smoking, diabetes mellitus, hypertension, and hypercholesterolemia can barely account for the high prevalence of cardiovascular disease.

At the beginning of the last century, Nikolai N. Anichkov demonstrated that cholesterol per se was able to produce atheromatous lesions in the vascular wall [1]. He also described the presence of inflammatory cells in the lesions, but these findings were dismissed for many decades. In 1995, Hansson and others established that atherosclerosis exhibited many features of a chronic inflammatory process, giving rise to the immune-mediated hypothesis behind atherogenesis [2]. At the time, however, preventive medicine was not a priority. Nowadays, such discoveries can be highly valuable in immune-mediated inflammatory disorders (IMID) in general, and in psoriasis (Ps) and psoriatic arthritis (PsA) in particular. It is known that adaptive and innate immunity participate in every step of atherogenesis. In fact, both traditional and non-traditional cardiovascular risk (CVR) factors increase in the course of these diseases [3]. This provides a comprehensive basis to explain the immune-mediated nature of atherogenesis beyond autoimmune condition while outlining the different crossroads of inflammation.

## **2. Psoriasis and psoriatic arthritis**

Psoriasis (Ps) and psoriatic arthritis (PsA) belong to the family of IMID, affecting predominantly skin and joints. The prevalence of Ps varies between 2 and 3% worldwide with a similar distribution according to sex [4]. Epidemiological studies show peak incidence between the second and third decades in life [5]. It has been estimated that 7–42% of Ps patients develop inflammatory arthropathy, usually manifesting as a mono or asymmetrical oligo-arthritis [6]. Substantial body of evidence suggests that PsA patients are at higher risk of developing atherosclerotic cardiovascular disease (CVD) [7–9] and mortality [10, 11]. To date, the pathogenesis of Ps and PsA remains unknown. Autoantigens have not been identified and the specificity of infiltrating lymphocytes is still unknown [2]. Genetically predisposed background and several suspected environmental triggering factors (e.g., infections, drugs, physical, and emotional stress) have been implicated in the initial stages of these diseases [9]. PsA is considered a seronegative (rheumatoid factor negative) arthritis. In Ps and PsA, the inflammatory features/reactions in skin and joints are very similar regarding composition of inflammatory infiltrates and vascular changes as explained in **Figure 1** [12]. Moreover, the cellular infiltrate is predominantly perivascular and due to mononuclear cells [13].

The contribution of B lymphocytes to Ps and PsA pathogenesis is poorly understood. However, none of the forms of Ps or PsA have been associated with serum auto-antibodies [14]. In contrast, T lymphocytes are the most abundant in both skin and the synovial fluid of joints, with Immune System Links Psoriasis-Mediated Inflammation to Cardiovascular Diseases via Traditional... http://dx.doi.org/10.5772/intechopen.68559 93

**Figure 1.** Schematic representation of the immune system-derived crosstalk between IMID and metabolic tissue, with events that worsen cardiovascular risk profile. Chronic inflammation of the skin and joints have many common immunopathological features, including genetic predisposition, composition of inflammatory infiltrates, vascular changes, early immune events, and proangiogenicity. Antigen is presented to naive CD4 T cells during immune synapse in the lymph node. Emerging lymphocytes migrate preferentially to skin and joints, where the above-mentioned infiltrating T lymphocytes (CD4 and CD8) interact with local APC (Langerhans cells, myeloid-DC, and plasmacytoid-DC) to produce chronic inflammatory conditions. Local re-activated T cells secrete chemokines and cytokines that amplify the inflammatory environment, resulting in the formation of psoriatic plaque, induction of cartilage degradation, and perhaps formation of atherosclerotic plaque. Since the suppressive activity of regulatory T cells is decreased in both tissue and blood, chronic production of proinflammatory cytokines (IFN-γ and TNF-α) crucially contributes to perpetuate the disease. In addition, deregulated adipose tissue (WAT) that secretes cytokines and chemokynes enhances systemic inflammatory burden leading to metabolic diseases (diabetes, metabolic syndrome, and dislipemia).

predominance of Tc1 (subpopulation of CD8+ cytotoxic T cells that secrete interferon (IFN) and IL-4), T-helper 1 lymphocyte subpopulation (Th1) and Th17 (IL-17+ T-helper cells) which interact with dendritic cells, macrophages, and target tissue cells [15]. Positive chemotaxis is observed between these cells and MCP-1 as found in synovial fluid [16] and skin biopsies obtained from Ps and PsA patients [17]. The role of lymphocytes in Ps and PsA pathogenesis is discussed later.

## **3. Atherosclerosis**

**Keywords:** psoriasis, psoriatic arthritis, inflammation, immune system, cardiovascular

Traditional cardiovascular risk factors like smoking, diabetes mellitus, hypertension, and hypercholesterolemia can barely account for the high prevalence of cardiovascular disease.

At the beginning of the last century, Nikolai N. Anichkov demonstrated that cholesterol per se was able to produce atheromatous lesions in the vascular wall [1]. He also described the presence of inflammatory cells in the lesions, but these findings were dismissed for many decades. In 1995, Hansson and others established that atherosclerosis exhibited many features of a chronic inflammatory process, giving rise to the immune-mediated hypothesis behind atherogenesis [2]. At the time, however, preventive medicine was not a priority. Nowadays, such discoveries can be highly valuable in immune-mediated inflammatory disorders (IMID) in general, and in psoriasis (Ps) and psoriatic arthritis (PsA) in particular. It is known that adaptive and innate immunity participate in every step of atherogenesis. In fact, both traditional and non-traditional cardiovascular risk (CVR) factors increase in the course of these diseases [3]. This provides a comprehensive basis to explain the immune-mediated nature of atherogenesis beyond autoimmune condition while outlining the different crossroads of inflammation.

Psoriasis (Ps) and psoriatic arthritis (PsA) belong to the family of IMID, affecting predominantly skin and joints. The prevalence of Ps varies between 2 and 3% worldwide with a similar distribution according to sex [4]. Epidemiological studies show peak incidence between the second and third decades in life [5]. It has been estimated that 7–42% of Ps patients develop inflammatory arthropathy, usually manifesting as a mono or asymmetrical oligo-arthritis [6]. Substantial body of evidence suggests that PsA patients are at higher risk of developing atherosclerotic cardiovascular disease (CVD) [7–9] and mortality [10, 11]. To date, the pathogenesis of Ps and PsA remains unknown. Autoantigens have not been identified and the specificity of infiltrating lymphocytes is still unknown [2]. Genetically predisposed background and several suspected environmental triggering factors (e.g., infections, drugs, physical, and emotional stress) have been implicated in the initial stages of these diseases [9]. PsA is considered a seronegative (rheumatoid factor negative) arthritis. In Ps and PsA, the inflammatory features/reactions in skin and joints are very similar regarding composition of inflammatory infiltrates and vascular changes as explained in **Figure 1** [12]. Moreover, the cellular infiltrate

The contribution of B lymphocytes to Ps and PsA pathogenesis is poorly understood. However, none of the forms of Ps or PsA have been associated with serum auto-antibodies [14]. In contrast, T lymphocytes are the most abundant in both skin and the synovial fluid of joints, with

risk factors

92 An Interdisciplinary Approach to Psoriasis

**2. Psoriasis and psoriatic arthritis**

is predominantly perivascular and due to mononuclear cells [13].

**1. Introduction**

Atherosclerosis is a complex inflammatory disease characterized by disturbances in the metabolic and immune system homeostasis that lead to pathogenic chronic progressive vascular damage and production of atherosclerosis plaque containing macrophages, lymphocytes, and other immune cells.

Classical knowledge distinguishes between inflammatory and non-inflammatory diseases. However, this distinction is no longer appropriate following the identification of inflammatory mechanisms associated with the traditionally called "non-inflammatory diseases."

Although atherogenesis belonged to this group for several decades, now it is confirmed that the immune system acts on the endothelial wall and triggers an inflammatory cascade, leading to a progressive low-grade inflammatory process of the arterial vascular wall in response to accumulation and oxidation of lipoproteins. Yet, further considerations pinpoint a prominent and severely pathogenic role of the immune system in these diseases [18].

Studies in hypercholesterolemia-induced immune activation in mouse models of atherosclerosis highlight the critical balance between Th1 cells [19] and Treg [20]. Inflammation in the intima layer appears to be related with protective and pathogenic immune responses against modified self-antigens in the atherosclerotic plaque [21].

The paradigm of atherosclerosis as an inflammatory disease is widely accepted. Interestingly, systemic inflammatory rheumatic diseases might share several immune-mediated inflammatory pathways with atherosclerosis. In fact, molecules and cells from innate and adaptive immune system (described below) mediate chronic inflammatory pathways activation derived from both diseases interacting in a positive feedback pathogenic circuit.

Increasing evidence suggests that even in clinically heterogeneous diseases, both of them could share common immunological pathways that might damage the cardiovascular (CV) system (**Table 1**). The contribution of chronic inflammation to CVR has mainly been investigated in rheumatoid arthritis (RA), the prototypical inflammatory disorder [22–24]. Consistently,



Although atherogenesis belonged to this group for several decades, now it is confirmed that the immune system acts on the endothelial wall and triggers an inflammatory cascade, leading to a progressive low-grade inflammatory process of the arterial vascular wall in response to accumulation and oxidation of lipoproteins. Yet, further considerations pinpoint a promi-

Studies in hypercholesterolemia-induced immune activation in mouse models of atherosclerosis highlight the critical balance between Th1 cells [19] and Treg [20]. Inflammation in the intima layer appears to be related with protective and pathogenic immune responses against

The paradigm of atherosclerosis as an inflammatory disease is widely accepted. Interestingly, systemic inflammatory rheumatic diseases might share several immune-mediated inflammatory pathways with atherosclerosis. In fact, molecules and cells from innate and adaptive immune system (described below) mediate chronic inflammatory pathways activation

Increasing evidence suggests that even in clinically heterogeneous diseases, both of them could share common immunological pathways that might damage the cardiovascular (CV) system (**Table 1**). The contribution of chronic inflammation to CVR has mainly been investigated in rheumatoid arthritis (RA), the prototypical inflammatory disorder [22–24]. Consistently,

> Higher prevalence for CHF, PVD, IHD atherosclerosis, type II diabetes, HL, and HTN in PsA patients than controls.

> Result compared against baseline before and after the end of treatment with Onercept. Results indicate higher CRP, that positively correlate with reduced Lp (a); higher ICAM-1; reduced IL6; reduced Homocysteine; same levels Apo-I¸ higher Apo-B, and higher TG.

> Carotid artery IMT correlated with age, time of PsA diagnosis, disease duration,

> Multivariate analysis indicates that PsA status, age, and TG levels were associated with IMT and carotid plaque.

Increased prevalence of DM and HTN was found in PsA group compared with age- and sex and BMI-matched controls.

The average IMT (mean/standard deviation) in PsA patients was significantly higher compared to CP even after adjustment for age, GR, BMI,

HTN, and HL.

total cholesterol, and LDL.

nent and severely pathogenic role of the immune system in these diseases [18].

derived from both diseases interacting in a positive feedback pathogenic circuit.

asimptomatic controls matched by age, sex, and geographic region.

at least first failure with DMARDS treatment, PsA- with 6 months duration or more with active arthritis in 3 or 4 swollen joints. Doubleblind placebo (*n* = 42) controlled study performed with two doses of

patients without clinically evident CVD adjusted for age and ethnia.

controls matched by age, sex, and

with PsA were compared with 43 healthy controls matched for age

Onercept for 12 weeks.

**Author, year Number of patients and study profile Findings**

Han et al., 2006 [33] 3066 PsA patients vs. clinically

Gonzalez-Juanatey et al., 2007 [35] 59 PsA patients vs. 59 control

Eder et al., 2008 [36] 40 PsA patients compared with 40

Tam et al., 2008 [37] 102 PsA patients from Southern

Kimhi et al., 2007 [38] Carotid artery IMT from 47 patients

CVR factors.

China.

and sex.

Sattar et al., 2007 [34] 127 patients with active Ps/PsA after

modified self-antigens in the atherosclerotic plaque [21].

94 An Interdisciplinary Approach to Psoriasis

AC: Alcohol consumption; BMI: Body mass index; CAD: Coronary artery disease; CCF: Controlled for confounding factors; CHF: Congestive heart failure; CP: Control population; CVD: Cardiovascular disease; DM: Diabetes mellitus; DMARDS: Disease-modifying antirheumatic drugs; ED: Endothelial dysfunction; GR: Gender: GP: General population; HDL: High-density lipoprotein; HL: Hyperlipidemia; HTN: Hypertension; ICAM-1: Intercellular adhesion molecule 1; IHD: Ischemic heart disease; IL6: Interleukin 6; LDL: Low-density lipoprotein; Lp (a): Lipoprotein A; MI: Myocardial infarction; OB: Obesity; PVD: Peripheral vascular disease; TC: Total cholesterol; TG: Triglycerides; TRF: Traditional risk factors; VLDL: Very low-density lipoprotein.

**Table 1.** Representative summary of epidemiological studies (prospective and retrospective) linking Ps to associated Cardiovascular Risk and Comorbidities (RCM), published between 2006 and 2016.

chronic activation of immune-mediated pathways is believed to accelerate or trigger critical atherosclerosis events in Ps and PsA.

A multidisciplinary expert committee was designated a few years ago in accordance with European League against Rheumatism (EULAR) suggests apart from the management of conventional risk factors, an aggressive inflammation suppressive therapy to further reduce [3] death in PsA patients [25]. Chronic inflammatory state seems to be the potential driving force behind the accelerated atherogenesis [26]. In this regard, few papers have been published related to CVR factors (**Table 1**) [7, 8, 27]. Some representative prospective and retrospective epidemiological surveys, published between 2006 and 2015 (**Table 1**), indicate that Ps and PsA patients exhibit higher prevalence of myocardial infarction (MI), ischemic heart disease, hypertension, diabetes, and dyslipidemia compared with normal controls. Although multiple CVR factors are associated with Ps, key components of the metabolic syndrome are more strongly connected with more severe Cutaneous psoriasis (PsC) [28]. Recent studies [29] suggest an increased inflammatory burden in PsA compared with Ps (**Table 1**). In contrast, the risk of developing a CV event (MI, ischemic stroke, and transient ischemic attack) was not elevated in early Ps patients in a matched follow-up study, casecontrol analysis [30, 31].

## **4. Inflammatory and classical cardiovascular risk factors**

## **4.1. Inflammatory risk factors**

Since a substantial amount of data accumulates in the past of this issue, we provide a brief insight into the most common inflammation-related and non-inflammatory factors involved in accelerated atherogenesis in Ps and PsA. As previously mentioned, Ps and atherosclerosis have a similar immune innate and adaptive pathogenic hallmark and an active crosstalk between "traditional" or "non-traditional" (**Figure 1**) [32].

## *4.1.1. Innate immunity*

Toll-like receptor 2 (TLR-2) and toll-like receptor 4 (TLR-4) trigger receptor-mediated events, including cytokine-mediated inflammation, are involved in atherosclerosis [44], Ps, and other pathologies [34]. TLR expression is positively correlated with plasma tumor necrosis factor-alpha (TNF-α) levels [45]. Cytokine-triggered TLRs activation is known to modulate major pathological processes, including inflammation, angiogenesis, tissue remodeling, and fibrosis. Although joints are the most obvious inflammation sites in PsA, proinflammatory cytokines, most likely TNF-α and interleukin 6 (IL-6), are released in blood circulation and act on distant organs (immune system, adipose tissue, liver, hematopoietic tissue, skeletal muscle, glands, and endothelium). These effects are linked to systemic inflammation and lead to a proatherogenic profile. Cytokines orchestrate endothelial adhesiveness, matrix metalloproteinases (MMPs) activation, reactive oxygen species (ROS) production, C-reactive protein (CRP), fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) release [46].

Indeed, atherogenic lipid alterations, oxidative stress abnormalities, vascular injury repair failure, arterial stiffness, insulin resistance induction, endothelial dysfunction, hypercoagulable state, homocysteine elevation, and pathogenic T cell up-regulation could all be attributed in part to the proinflammatory actions of cytokines. Common inflammatory mechanisms in Ps and atherosclerosis may be related to other factors by the high number of overlapping molecules, including cytokines [interleukins (IFN-α, IL-2, IL-6, IL-10, IL-13, IL-15, IL-17, IL-18, IL-20, and IL-23)], interferon alpha (IFN-α), Oncostatin M, (TNF-α), chemokines [Fractalkine, growth-regulated oncogene (GRO) alpha], CCL-3(MIP-1α), CCL-4 (MIP-1α), CCL-11 (Eotaxin), IL-8, MCP-1, monokine induced by interferon gamma (MIG/CXCL9), adipokines (Resistin, Leptin, and PAI-1), adhesion molecules (ICAM/LFA-1(leukocyte function-associated antigen-1), CD154 (OX40L)/CD134 (OX40), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), fibroblast growth factors (FGF), and GCSF, co-stimulatory molecules (CD80, CD28, and CD40/CD40L), lymphocyte profile Th1/Th17 up-regulation, Treg down-regulation, CTL effect or activity, NK cells, natural killer T (NKT) cells, myeloid dendritic cells, plasmacytoid dendritic cells, monocytes/macrophages, mast cells and neutrophils, complement activation [47], TLR-mediated inflammation (TLR-2, TLR-4, and TLR-9) [27–29], and other important factors, such as CRP, endothelin-1, inducible nitric oxide synthase (iNOS), heat shock protein (HSP60, HSP65, and HSP70), matrix metalloproteinases (MMP-2 and MMP-9), and oxidized low-density lipoprotein (LDL) [45, 48, 49]. Some molecules listed before and other PsA-related serum cytokine patterns have been demonstrated by multiplex cytokine array systems in Norwegian PsA patients [50, 51]. Few of these cytokines previously mentioned [52, 53] and their pathogenic contribution at different stages in the pathobiology of atherothrombosis and PsA are not clear yet [36].

NK cells increase the susceptibility to PsA [51] and the inflammatory infiltrate in psoriatic skin lesions. Although more studies must be done, emerging evidence supports a role for NK cells in Ps. Inverse correlation exists between NK cell population and body mass index (BMI). Therefore, adipose immune cell phenotype and function may provide greater insight into cardio-metabolic pathophysiology in psoriasis [54, 55].

NKT cells are a heterogeneous subset of T cell lineage lymphocytes that bear NK cell molecules and T cell receptors, which recognize microbial glycolipids and their own endogenous mammalian lipids presented by the MHC I-like molecule (CD1d) and have been implicated in the pathogenesis of various autoimmune diseases including Ps. Due to the numerous functions of NKT cells that link innate and adaptive immunity, their role in Ps is complex and still elusive. ApoE and LDL receptors have been involved in antigen uptake for presentation to NKT cells [56] NKT cells may represent a potential new therapy for atherosclerosis [57].

Our knowledge of biologically active serum molecules and cells involved in the pathogenesis of both PsA and atherosclerosis is still not clear enough. Taken together, cytokines seem to play a pivotal role as the major link between PsA and atherosclerosis. Compiled data show that untreated PsA inflammation could produce damage to the CV system even before it affects the joints [50]. Current evidence suggests that the pathway of inflammation in atherosclerosis culminates in altered concentrations of various markers in peripheral blood, including oxidative stress molecules [58–60] and markers of vascular inflammation like CRP [59], IL-6, ICAM-1, and MCP-1 [61].

## *4.1.1.1. Tumor necrosis factor-α*

retrospective epidemiological surveys, published between 2006 and 2015 (**Table 1**), indicate that Ps and PsA patients exhibit higher prevalence of myocardial infarction (MI), ischemic heart disease, hypertension, diabetes, and dyslipidemia compared with normal controls. Although multiple CVR factors are associated with Ps, key components of the metabolic syndrome are more strongly connected with more severe Cutaneous psoriasis (PsC) [28]. Recent studies [29] suggest an increased inflammatory burden in PsA compared with Ps (**Table 1**). In contrast, the risk of developing a CV event (MI, ischemic stroke, and transient ischemic attack) was not elevated in early Ps patients in a matched follow-up study, case-

Since a substantial amount of data accumulates in the past of this issue, we provide a brief insight into the most common inflammation-related and non-inflammatory factors involved in accelerated atherogenesis in Ps and PsA. As previously mentioned, Ps and atherosclerosis have a similar immune innate and adaptive pathogenic hallmark and an active crosstalk

Toll-like receptor 2 (TLR-2) and toll-like receptor 4 (TLR-4) trigger receptor-mediated events, including cytokine-mediated inflammation, are involved in atherosclerosis [44], Ps, and other pathologies [34]. TLR expression is positively correlated with plasma tumor necrosis factor-alpha (TNF-α) levels [45]. Cytokine-triggered TLRs activation is known to modulate major pathological processes, including inflammation, angiogenesis, tissue remodeling, and fibrosis. Although joints are the most obvious inflammation sites in PsA, proinflammatory cytokines, most likely TNF-α and interleukin 6 (IL-6), are released in blood circulation and act on distant organs (immune system, adipose tissue, liver, hematopoietic tissue, skeletal muscle, glands, and endothelium). These effects are linked to systemic inflammation and lead to a proatherogenic profile. Cytokines orchestrate endothelial adhesiveness, matrix metalloproteinases (MMPs) activation, reactive oxygen species (ROS) production, C-reactive protein

Indeed, atherogenic lipid alterations, oxidative stress abnormalities, vascular injury repair failure, arterial stiffness, insulin resistance induction, endothelial dysfunction, hypercoagulable state, homocysteine elevation, and pathogenic T cell up-regulation could all be attributed in part to the proinflammatory actions of cytokines. Common inflammatory mechanisms in Ps and atherosclerosis may be related to other factors by the high number of overlapping molecules, including cytokines [interleukins (IFN-α, IL-2, IL-6, IL-10, IL-13, IL-15, IL-17, IL-18, IL-20, and IL-23)], interferon alpha (IFN-α), Oncostatin M, (TNF-α), chemokines [Fractalkine, growth-regulated oncogene (GRO) alpha], CCL-3(MIP-1α), CCL-4 (MIP-1α), CCL-11 (Eotaxin), IL-8, MCP-1, monokine induced by interferon gamma (MIG/CXCL9), adipokines

(CRP), fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) release [46].

**4. Inflammatory and classical cardiovascular risk factors**

between "traditional" or "non-traditional" (**Figure 1**) [32].

control analysis [30, 31].

96 An Interdisciplinary Approach to Psoriasis

**4.1. Inflammatory risk factors**

*4.1.1. Innate immunity*

The pleiotropic cytokine TNF-α is among the most potent mediators of inflammation. Circulating T lymphocytes and monocyte-derived macrophages isolated from PsA patients produce increased amounts of TNF-α in comparison with macrophages isolated from healthy controls [8]. Furthermore, levels of TNF-α in PsA patients are elevated in the synovial tissue and skin lesions and correlate with disease activity. TNF-α is a key regulator of vascular homoeostasis [34], leading to proatherogenic effects, lipid abnormalities, including high LDL cholesterol and low HDL cholesterol [62], hypercoagulable state via induction of cell surface expression of tissue factor (TF) on the endothelial wall and suppress anticoagulant activity via the thrombomodulin-activated protein C system [63]. The majority of epidermal CTL and Th1 effector lymphocyte populations and molecules are elevated in Ps vulgaris lesions and in circulating blood in psoriatic patients [64]. TNF-α also induces endothelial dysfunction including low nitric oxide availability and up-regulation of endothelial adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1) [65, 66], a critical early step in atherogenesis. On the other hand, TNF-α blockade leads to a significant decrease in the levels of lipoprotein a (Lpa) homocysteine and an increase in apolipoprotein A-I (Apo A-I), triglyceride, and Apo-B concentration [62]. Long-term use of TNF-α blocking agents interferes with TNF-α function reducing the high incidence of cardiovascular events and associated vascular complications in CV diseases [67]. Taken together, the above-mentioned studies confirm a critical role for TNF-α in altering a number of well-studied putative vascular, thrombotic, and metabolic risk parameters (lipids and lipoproteins).

#### *4.1.1.2. Interleukin 6*

As an inflammatory cytokine, IL-6 regulates chemokine-directed leukocyte trafficking and directs transition from innate to adaptive immunity through the regulation of leukocyte activation, differentiation, and proliferation [68]. During acute and chronic inflammatory response, macrophages release TNF-α in the presence of a great variety of stimuli, including atherogenic and poorly characterized arthritogenic factors. TNF-α action on macrophages triggers the release of more TNF-α and IL1-β, which stimulate endothelial cells to produce IL-6 and IL-8. IL-6 and their signaling events contribute to hepatic release of acute-phase reactants including CRP levels, atherosclerotic plaque development and destabilization [69, 70]. IL-6 may also contribute to atherosclerosis and arterial thrombosis by activating the production of tissue factor, fibrinogen and factor VIII; increasing endothelial cell adhesiveness and stimulating platelet production and aggregation [71]. In addition, IL-6 is produced by smooth muscle cells (SMC) of many blood vessels and by adipocytes and, together with CRP and TNF-α, is involved in metabolic syndrome pathophysiology, insulin resistance [72] and coronary artery disease and the risk of MI [73–76], and cardiovascular mortality [77]. In addition, IL-6 locally produced in the endothelium and in SMC is an important autocrine and paracrine regulator of SMC proliferation and migration. IL-6 decreases cardiac contractility via a nitric oxide (NO)-dependent pathway activating STAT3-dependent anti-inflammatory signal transduction [78].

Numerous studies show a strong association between IL-6 and joint immune-mediated diseases. In the joint, macrophages and mast cells trigger a proinflammatory cascade in the presence of unknown stimuli, releasing great amounts of TNF-α, which induce the expression of IL-1 and IL-6. Mice deficient in mast cells are comparatively resistant in experimentally induced arthritis. In addition, it is a major promoter of bone resorption in pathological conditions [79]. In particular, IL-6 has a pivotal role in synovitis, bone erosion, and in the systemic features of inflammation [80].

In Ps, most available evidence indicates that the pathogenic action of IL-6 is important. In fact, IL-6 co-localizes with CD45+ perivascular cells within lesional tissue and reverses the suppressive function of human T-regulatory cells [81].

The successful treatment of certain autoimmune conditions with the humanized antibody anti-IL-6 receptor (IL-6R) (Tocilizumb) has emphasized the clinical importance of cytokines that signal through the β-receptor subunit glycoprotein 130 [82].

IL-6 may, in both cardiovascular and joint-diseases involving Th1/Th17 mechanisms, alter the balance between the effector and regulatory arms of the immune system and drive a proinflammatory phenotype reinforcing innate and adaptive immune-mediated positive feedback [83], potentiating the immune effector mechanism. In both arterial disease and Ps/PsA, IL-6 seems to be a critical mediator of long-term chronic inflammation and to have deleterious effect in the arterial wall and in the joint.

## *4.1.1.3. Endothelin-1*

and low HDL cholesterol [62], hypercoagulable state via induction of cell surface expression of tissue factor (TF) on the endothelial wall and suppress anticoagulant activity via the thrombomodulin-activated protein C system [63]. The majority of epidermal CTL and Th1 effector lymphocyte populations and molecules are elevated in Ps vulgaris lesions and in circulating blood in psoriatic patients [64]. TNF-α also induces endothelial dysfunction including low nitric oxide availability and up-regulation of endothelial adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1) [65, 66], a critical early step in atherogenesis. On the other hand, TNF-α blockade leads to a significant decrease in the levels of lipoprotein a (Lpa) homocysteine and an increase in apolipoprotein A-I (Apo A-I), triglyceride, and Apo-B concentration [62]. Long-term use of TNF-α blocking agents interferes with TNF-α function reducing the high incidence of cardiovascular events and associated vascular complications in CV diseases [67]. Taken together, the above-mentioned studies confirm a critical role for TNF-α in altering a number of well-studied putative vascular, thrombotic, and metabolic risk

As an inflammatory cytokine, IL-6 regulates chemokine-directed leukocyte trafficking and directs transition from innate to adaptive immunity through the regulation of leukocyte activation, differentiation, and proliferation [68]. During acute and chronic inflammatory response, macrophages release TNF-α in the presence of a great variety of stimuli, including atherogenic and poorly characterized arthritogenic factors. TNF-α action on macrophages triggers the release of more TNF-α and IL1-β, which stimulate endothelial cells to produce IL-6 and IL-8. IL-6 and their signaling events contribute to hepatic release of acute-phase reactants including CRP levels, atherosclerotic plaque development and destabilization [69, 70]. IL-6 may also contribute to atherosclerosis and arterial thrombosis by activating the production of tissue factor, fibrinogen and factor VIII; increasing endothelial cell adhesiveness and stimulating platelet production and aggregation [71]. In addition, IL-6 is produced by smooth muscle cells (SMC) of many blood vessels and by adipocytes and, together with CRP and TNF-α, is involved in metabolic syndrome pathophysiology, insulin resistance [72] and coronary artery disease and the risk of MI [73–76], and cardiovascular mortality [77]. In addition, IL-6 locally produced in the endothelium and in SMC is an important autocrine and paracrine regulator of SMC proliferation and migration. IL-6 decreases cardiac contractility via a nitric oxide (NO)-dependent pathway activating STAT3-dependent anti-inflammatory

Numerous studies show a strong association between IL-6 and joint immune-mediated diseases. In the joint, macrophages and mast cells trigger a proinflammatory cascade in the presence of unknown stimuli, releasing great amounts of TNF-α, which induce the expression of IL-1 and IL-6. Mice deficient in mast cells are comparatively resistant in experimentally induced arthritis. In addition, it is a major promoter of bone resorption in pathological conditions [79]. In particular, IL-6 has a pivotal role in synovitis, bone erosion, and in the systemic

parameters (lipids and lipoproteins).

98 An Interdisciplinary Approach to Psoriasis

*4.1.1.2. Interleukin 6*

signal transduction [78].

features of inflammation [80].

The family of endothelins (ET) includes three 21-aminoacid isoforms endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3), which have endogenous pressor activity and are secreted by different tissues and cells. In addition, ET-1 is a vasoactive peptide that induces vasoconstriction, inflammation, and fibrosis and has mitogenic potential for SMC [84]. In the skin, ET-1 participates in keratinocyte proliferation, neoangiogenesis, and chemotaxis. Its levels are elevated in psoriatic lesions and serum of patients with Ps [85]. Synovial tissue and serum of patients with PsA all show strongly enhanced ET-1 receptor expression [86].

## *4.1.1.4. C-reactive protein*

A considerable amount of evidence implicates C-reactive protein (CRP) as a predictive marker for future CV events and mortality in different settings, particularly under metabolic syndrome conditions in the general population [87, 88]; CRP has also been implicated as a direct partaker [7, 89, 90]. In addition, CRP stimulates the production of plaque destabilizing MMPs and MCP-1, a decrease in the activity of endothelial nitric oxide synthase (eNOS) and impairment in endothelium dependent vasodilation [91]. In vitro, studies provide evidence for direct proatherogenic effects of CRP, including increased endothelial dysfunction [92]. Baseline CRP levels were elevated in patients with Ps with and without psoriatic arthritis and Etanercept, a biologic TNF antagonist, treatment may reduce CRP levels in both groups [93].

## *4.1.1.5. Adipokines*

Interestingly, in metabolic disorders associated with Ps/PsA, inflamed adipose tissue may enhance inflammatory proatherogenic status via adipokine production (leptin, adiponectin, and resistin) and cytokine (TNF-α and IL-6) secretion. Adipose tissue influences both natural and adaptive immunities and links inflammation, metabolic dysfunction, and cardiovascular disease [94].

## *4.1.1.6. Matrix metalloproteinases (MMPs)*

MMPs are endoproteases with collagenase and/or gelatinase activity which exert deleterious effects on the endothelium integrity and collagen fibers, promoting atherosclerotic plaque destabilization and accelerating the process of atherothrombosis [95]. MMP-1 serum levels and gene expression are elevated in PsA [96].

## *4.1.2. Adaptive immunity*

As previously mentioned, Ps/PsA and atherosclerosis share certain common underlying pathogenic inflammatory mechanisms. Specifically, both are associated with Th1 and CTL (cytotoxic T lymphocyte) effector cell-mediated events in vivo [68], and are elevated in circulating blood [63]. In contrast, the T-regulatory activity is reduced.

#### *4.1.2.1. Cellular immune response*

Myeloid dendritic cells can stimulate both memory and naive T cells, and are the most potent of all the antigen-presenting cells in normal and various pathophysiological conditions [97]. In turn, activated T cells undergo firm adhesion and transendothelial migration to inflammatory focus. Extravasation is orchestrated by the combined action of cellular adhesion receptors and chemotactic factors in a wide variety of cardiovascular and autoimmune disorders that involve inflammation.

The development and maintenance of psoriatic plaque are dependent on the participation of infiltrating T lymphocytes (CD4 and CD8) and local antigen-presenting cells (APCs) (Langerhans cells, myeloid, and plasmacytoid-DC). DCs are increased in psoriatic lesions and are critically involved in the induction of Th1 and Th17 cell proliferation, which, in turn, release IFN-γ and IL-17, respectively. Activated mDCs produce IL-23 [98, 99] and TNF-α. IL-23 stimulates the secretion of IL-22 by Th17 cells, which may be involved in epidermal hyperplasia [5]. The effects of IL-17A-producing T-helper 17 (Th17) cells include suppressive effects of T-regulatory (Treg) subsets, which have also been implicated in both pathologies. The association of IL-17A with Ps and PsA has been extensively described [98, 99] and a growing body of evidence suggests that IL-17A might also be involved in atherosclerosis [100]. IL-17 seems to have a modulatory role in atherosclerosis, but studies available show contrasting results, which could be attributed to different approaches and models. Coronary syndrome correlates with increased IL-17 levels [101]. In addition, TNF-α and IL-17 synergistically up-regulate further cytokine transcription in both diseases, Ps and atherogenesis [102]. These observations make IL-17A an interesting therapeutic target to modulate both PsA/Ps disease activity and atherosclerosis/cardiovascular risk. Obesity may play an important role by amplifying the inflammation of arthritis through the Th1/Th17 response [103]. Limited evidence from Ps patients indicates that induction therapy with infliximab, with moderate to severe plaque Ps, led to decrease in clinical disease scores and circulating levels of Th17, Th1 cells, and associated TNF-α release [104].

T cell activation is under control from T-regulatory immune cell (Treg) activity via IL-10 and TGF-β [105–107]. Reduced numbers and/or activity of Treg cells may produce hyperactivity of Th1/Th17 subsets in both pathologies [21, 108, 109]. Ps and coronary artery disease patients show impaired inhibitory function of Treg [110, 111]. Serum and epidermal levels [105, 106] of TGF-β in Ps patients are associated with Ps disease severity [112, 113] and are diminished in low Ps [5]. In atherosclerosis, high serum levels of TGF-β and IL-10 may inhibit plaque formation [114, 115] and plaque stabilization exerting protective effect due its inhibition of T cells [116].

## *4.1.2.2. Humoral immune response*

*4.1.1.6. Matrix metalloproteinases (MMPs)*

and gene expression are elevated in PsA [96].

lating blood [63]. In contrast, the T-regulatory activity is reduced.

*4.1.2. Adaptive immunity*

100 An Interdisciplinary Approach to Psoriasis

*4.1.2.1. Cellular immune response*

that involve inflammation.

cells, and associated TNF-α release [104].

MMPs are endoproteases with collagenase and/or gelatinase activity which exert deleterious effects on the endothelium integrity and collagen fibers, promoting atherosclerotic plaque destabilization and accelerating the process of atherothrombosis [95]. MMP-1 serum levels

As previously mentioned, Ps/PsA and atherosclerosis share certain common underlying pathogenic inflammatory mechanisms. Specifically, both are associated with Th1 and CTL (cytotoxic T lymphocyte) effector cell-mediated events in vivo [68], and are elevated in circu-

Myeloid dendritic cells can stimulate both memory and naive T cells, and are the most potent of all the antigen-presenting cells in normal and various pathophysiological conditions [97]. In turn, activated T cells undergo firm adhesion and transendothelial migration to inflammatory focus. Extravasation is orchestrated by the combined action of cellular adhesion receptors and chemotactic factors in a wide variety of cardiovascular and autoimmune disorders

The development and maintenance of psoriatic plaque are dependent on the participation of infiltrating T lymphocytes (CD4 and CD8) and local antigen-presenting cells (APCs) (Langerhans cells, myeloid, and plasmacytoid-DC). DCs are increased in psoriatic lesions and are critically involved in the induction of Th1 and Th17 cell proliferation, which, in turn, release IFN-γ and IL-17, respectively. Activated mDCs produce IL-23 [98, 99] and TNF-α. IL-23 stimulates the secretion of IL-22 by Th17 cells, which may be involved in epidermal hyperplasia [5]. The effects of IL-17A-producing T-helper 17 (Th17) cells include suppressive effects of T-regulatory (Treg) subsets, which have also been implicated in both pathologies. The association of IL-17A with Ps and PsA has been extensively described [98, 99] and a growing body of evidence suggests that IL-17A might also be involved in atherosclerosis [100]. IL-17 seems to have a modulatory role in atherosclerosis, but studies available show contrasting results, which could be attributed to different approaches and models. Coronary syndrome correlates with increased IL-17 levels [101]. In addition, TNF-α and IL-17 synergistically up-regulate further cytokine transcription in both diseases, Ps and atherogenesis [102]. These observations make IL-17A an interesting therapeutic target to modulate both PsA/Ps disease activity and atherosclerosis/cardiovascular risk. Obesity may play an important role by amplifying the inflammation of arthritis through the Th1/Th17 response [103]. Limited evidence from Ps patients indicates that induction therapy with infliximab, with moderate to severe plaque Ps, led to decrease in clinical disease scores and circulating levels of Th17, Th1 Humoral response seems to protect rather than harm the host. Several lines of evidence support the hypothesis that humoral immunity protects patients against atherosclerosis. First, the injection of immunoglobulin preparations inhibits atherosclerosis. Second, spleen removal (a B-cell rich lymphoid organ) seems to deteriorate vascular disease condition. Third, oxidized LDL plus adjuvant immunization promote atheroprotection [2]. Evidence so far indicates that atheroprotection is due to a T cell dependent B-cell-mediated mechanism, probably involving antibody dependent clearance of LDL and humoral dependent regulation of pathogenic T cell [17]. This atheroprotective response must be confirmed in humans.

## *4.1.3. Genes related to the innate and adaptive immune system associated with psoriasis and atherogenesis*

At least 10 chromosomal locus associated with psoriasis have been identified as PSORS (PSORS, psoriasis susceptibility) [117]. Additionally, certain human leucocyte antigen (HLAs) are more common in psoriatic arthritis. HLA alleles that are specific for psoriatic arthritis are HLA-B27 and possibly HLA-B7, HLA-B38, and HLA-B39.

There is a strong association of psoriasis with the HLA-Cw6 allele, which increases 10–20 times the risk of psoriasis and is present in 90% of the patients with early onset psoriasis and in 50% of those with late onset psoriasis [118].

Some molecules of the innate immune system have an important influence on the pathophysiology of psoriasis, such as TLR2 and TLR4 play a key role in the pathogenesis of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome, psoriasis, multiple sclerosis, and autoimmune diabetes [119].

Additionally, the expression of TLR2 and TLR4 correlates with the degree and severity of coronary disease [120, 121] oxidized phospholipids stimulate the TLR signaling pathway to induce inflammatory cytokine secretion by macrophages and endothelial cells [122].

Anti-CD14 and anti-TLR antibodies significantly inhibit the binding of fluorescein-labeled LDL to monocytes and interfering with cytokine release [123]. TNF-binding proteins are encoded by genes unrelated to PSORS, conferring susceptibility to psoriasis. Tumor necrosis factor, alpha-induced protein 3 (TNFAIP3) and tumor necrosis factor interacting protein 1 (TNIP1) are related to the inflammatory signal NF-κB, which regulates the release of TNF-α [124, 125].

TNFAIP3 promotes the survival of T-CD4 lymphocytes [126]. Certain cytokine genes have been implicated with psoriasis, including IL-12, IL-23, IL-4/IL-13 [127] conferring an increased risk of psoriatic arthritis [128].

These genes strengthened the assertion that psoriasis is an immune disorder, as these genes are linked to both the innate and adaptive immune response [129–131]. In summary, defects in these genes could amplify an inflammatory response by interfering with normal negative feedback of the NF-kB signal and therefore would link to psoriasis with other IMID and coronary pathology.

#### **4.2. Non-inflammatory risk factors**

Ps, PsA, and atherosclerosis share disturbances in different metabolic pathways involving insulin-dependent diabetes mellitus (IDDM), dyslipidemia, hypertension, obesity, and mostly metabolic syndrome, which may be related to an increase in the prevalence of CVD to their capability of inducing inflammation on the endothelial lining to initiate the process of atherosclerosis. So far, no pathophysiological mechanism for this association has been identified [63].

## *4.2.1. Hypertension*

Several studies have found an increase in the prevalence of hypertension in Ps patients, although the definition of hypertension is very heterogeneous among these studies [117–121, 132]. Other authors have not observed a significant association between Ps and hypertension [122].

#### *4.2.2. Diabetes mellitus*

IDDM is responsible for metabolic alterations, accompanied by chronic inflammation and endothelium dysfunction. Observational studies show that the risk of IDDM is higher in patients with Ps compared with a healthy control group. This risk increases with the duration and severity of Ps and it is not related to a high body mass index (BMI) alone [133]. In a case-control study from Israel, the risk of diabetes was significantly higher in individuals with Ps [124]. Similarly, PsA patients have a higher prevalence of IDDM, even after adjusting for the BMI [125]. TNF-α antagonist therapy in patients with Ps seems to improve insulin sensitivity in limited preliminary data [126]. Finally, a few isolated cases of Ps patients with diabetes develop unpredictable hyperglycemia after starting treatment with TNF-α inhibitors [127].

#### *4.2.3. Obesity*

Recent studies have shown that obesity may precede the onset of Ps as a risk factor [120], whereas a higher BMI is associated with more severe skin disease activity [3]. The influence of obesity on psoriatic diseases is the result of complex interactions of inflammatory and metabolic factors. The proinflammatory cytokines stimulate adipocytes to synthesize neuropeptides and more cytokines, which are critical in the pathogenesis of the psoriatic and CVD [69].

## *4.2.4. Smoking*

TNFAIP3 promotes the survival of T-CD4 lymphocytes [126]. Certain cytokine genes have been implicated with psoriasis, including IL-12, IL-23, IL-4/IL-13 [127] conferring an increased

These genes strengthened the assertion that psoriasis is an immune disorder, as these genes are linked to both the innate and adaptive immune response [129–131]. In summary, defects in these genes could amplify an inflammatory response by interfering with normal negative feedback of the NF-kB signal and therefore would link to psoriasis with other IMID and coro-

Ps, PsA, and atherosclerosis share disturbances in different metabolic pathways involving insulin-dependent diabetes mellitus (IDDM), dyslipidemia, hypertension, obesity, and mostly metabolic syndrome, which may be related to an increase in the prevalence of CVD to their capability of inducing inflammation on the endothelial lining to initiate the process of atherosclerosis. So far, no pathophysiological mechanism for this association has been identi-

Several studies have found an increase in the prevalence of hypertension in Ps patients, although the definition of hypertension is very heterogeneous among these studies [117–121, 132]. Other

IDDM is responsible for metabolic alterations, accompanied by chronic inflammation and endothelium dysfunction. Observational studies show that the risk of IDDM is higher in patients with Ps compared with a healthy control group. This risk increases with the duration and severity of Ps and it is not related to a high body mass index (BMI) alone [133]. In a case-control study from Israel, the risk of diabetes was significantly higher in individuals with Ps [124]. Similarly, PsA patients have a higher prevalence of IDDM, even after adjusting for the BMI [125]. TNF-α antagonist therapy in patients with Ps seems to improve insulin sensitivity in limited preliminary data [126]. Finally, a few isolated cases of Ps patients with diabetes develop unpredictable hyperglycemia after starting treatment with TNF-α inhibi-

Recent studies have shown that obesity may precede the onset of Ps as a risk factor [120], whereas a higher BMI is associated with more severe skin disease activity [3]. The influence of obesity on psoriatic diseases is the result of complex interactions of inflammatory and metabolic factors. The proinflammatory cytokines stimulate adipocytes to synthesize neuropeptides and more cytokines, which are critical in the pathogenesis of the psoriatic and CVD [69].

authors have not observed a significant association between Ps and hypertension [122].

risk of psoriatic arthritis [128].

102 An Interdisciplinary Approach to Psoriasis

**4.2. Non-inflammatory risk factors**

nary pathology.

fied [63].

tors [127].

*4.2.3. Obesity*

*4.2.1. Hypertension*

*4.2.2. Diabetes mellitus*

Heavy and long-term smoking [128] have been associated with increased Ps risk in both men and women [129], particularly pustular Ps [116, 117, 120]. Smoking increases oxidative damage, promotes inflammatory changes, and enhances Ps-associated gene expression [121] and CVR [50, 122].

## *4.2.5. Dyslipidemia*

Ps patients have a higher prevalence of dyslipidemia and triglycerides and lower prevalence of HDL levels. However, associations with total cholesterol and LDL have not been found statistically significant in a multivariate analysis study [116–118].

## *4.2.6. Metabolic syndrome*

The metabolic syndrome consists of a constellation of clinical features involving abdominal obesity (waist circumference from >94 cm in men and >80 cm in women), and two or more of the following clinical situations:

HDL ≤ 40 mg/dl in men and 50 mg/dl in women, TG > 150 mg/dl, fasting blood glucose > 100 mg/ dl, blood pressure > 130/85 mm Hg or treatment for hypertension. The metabolic syndrome is characterized by increases in the immunological activity of Th1, which suggests it may be associated with Ps because of shared inflammatory pathways.

Gisondi et al. [134] reported that, among Ps patients without systemic medication, 40-year-old and older people have a higher prevalence of metabolic syndrome [124].

Recently, Raychaudhuri et al. observed an increased prevalence of metabolic syndrome in patients with PsA; DM type 2 [58] and increased risk for CVD and mortality [125–129]. Ps with metabolic syndrome [130] associates with high serum uric acid levels that correlate with an increased risk of carotid intima-media thickness (IMT) or with the presence of carotid plaques [131].

## **5. Common angiogenic factors for Ps and atherosclerosis**

Angiogenesis appears to be pathological in some chronic inflammatory diseases, like Ps and RA. It is possible for reactive homeostatic or pathological angiogenesis to play an important role in atherosclerosis. Serum levels of proangiogenic cytokines (TGF-β, TNF-α, IL-8, and IL-17), growth factors, including VEGF, and hypoxia-induced factor-1 have been shown to be significantly elevated in Ps patients compared to healthy controls [132, 133].

## **6. Oxidative mechanisms common to atherosclerosis and Ps**

Cellular deregulation and damage [51] could be the result of overproduction or insufficient removal of ROS. In the skin, ROS can be generated either endogenous or exogenously. Endogenously, ROS are produced through the electron transport chain and enzymes, such as cyclooxygenases (COX) [33], lipoxygenases [38], NADPH oxidases [135], and myeloperoxidases [39]. Exogenous sources that trigger ROS production include UV radiation and heavy metals [51]. In Ps, antioxidant defense mechanisms seem to be impaired, including superoxide dismutases (SODs), glutathione peroxidases, glutathione reductase, catalase, thioredoxin/thioredoxin reductase system, and metallothioneins. Augmented ROS production in the skin leads to downstream molecular events that promote atherosclerosis [51, 136, 137].

The antioxidant activity of vitamin D is well known/widely characterized. The knowledge of non-classical functions emerges from studies that indicate a close association between a low vitamin D status and increased risk of IMID and CVD [138]. It is also known that vitamin D insufficiency induces metabolic, procoagulant, and inflammatory perturbations. Recent studies indicate that it also increases the risk of MI by promoting established CVR factor-mediated mechanisms that predispose to atherothrombosis [139].

Immunomodulatory role of vitamin D in human health implicates appropriate signaling for both innate and adaptive immune responses (T and B lymphocyte function) [140–142] that amplify inflammation in Ps [143] and promote the development of different types of Treg cells [144].

## **7. Some lessons from CVD and rheumatic-associated therapies**

Whether antirheumatic therapies increase or decrease CV risk is controversial. Glucocorticoids (GCs) are known to cause hypercholesterolemia, hypertriglyceridemia, weight gain, hypertension, and glucose intolerance, all factors promoting CVD. However, GCs are not ever conflicting. In RA patients with a known history of CVD, steroid therapy surprisingly attenuated the risk of CV death [145]. The mechanism of this apparent discrepancy with GC exposure is still unknown, but it seems to be related with dose, duration, and intensity of the exposure.

Although coronary artery disease and acute myocardial infarction are inflammatory disorders, the only drugs with anti-inflammatory effect so far widely used in ischemic heart disease are aspirin and statins (e.g., atorvastatin and simvastatin).

The contribution of coxibs and most nonsteroidal anti-inflammatory drugs (NSAIDs) to lowering CVR is not well established and the evidence available so far is controversial. Multiple studies provide evidence that methotrexate is protective against CV events and CV mortality, although the protective benefit is under discussion [146]. Immunomodulatory or immunosuppressive therapies, such as cyclosporine and colchicine, may have benefits in coronary artery disease [147]. Other studies have found that glucocorticoids plus cytotoxic immunosuppressive agents (azathioprine, cyclosporine, and leflunomide) are associated with an increased amount of CV events when compared with methotrexate alone [148].

The new targeted biological therapies, such as the suppression of systemic inflammation by anti-TNF therapies, seem to be associated with concomitant reduction in the risk of CV events [149], although the effect of TNF-α antagonists in lowering proatherogenic status needs further investigation. In addition, cardiovascular therapy drugs could change the proinflammatory status of PsA patients under treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), angiotensin converting-enzyme (ACE) inhibitors, and/or angiotensin II receptor antagonists (AT-II blockers). Hence, their prescription should be managed cautiously, especially for patients with a documented CV disease or in the presence of CVR factors.

Other drugs with potential benefits may include the thiazolidinedione (TZD) family, which produces positive effects on both CVR factors and Ps [14]. Targeted therapeutic interventions along with an effective control of the inflammation may have more beneficial CV effects than direct CV toxicity. There is a need for more studies addressing the role of current biological therapies on patients with a CV risk profile [3].

## **8. The central role of the immune system**

Endogenously, ROS are produced through the electron transport chain and enzymes, such as cyclooxygenases (COX) [33], lipoxygenases [38], NADPH oxidases [135], and myeloperoxidases [39]. Exogenous sources that trigger ROS production include UV radiation and heavy metals [51]. In Ps, antioxidant defense mechanisms seem to be impaired, including superoxide dismutases (SODs), glutathione peroxidases, glutathione reductase, catalase, thioredoxin/thioredoxin reductase system, and metallothioneins. Augmented ROS production in the skin leads to downstream molecular events that promote atherosclerosis [51,

The antioxidant activity of vitamin D is well known/widely characterized. The knowledge of non-classical functions emerges from studies that indicate a close association between a low vitamin D status and increased risk of IMID and CVD [138]. It is also known that vitamin D insufficiency induces metabolic, procoagulant, and inflammatory perturbations. Recent studies indicate that it also increases the risk of MI by promoting established CVR factor-mediated

Immunomodulatory role of vitamin D in human health implicates appropriate signaling for both innate and adaptive immune responses (T and B lymphocyte function) [140–142] that amplify inflammation in Ps [143] and promote the development of different types of Treg cells [144].

Whether antirheumatic therapies increase or decrease CV risk is controversial. Glucocorticoids (GCs) are known to cause hypercholesterolemia, hypertriglyceridemia, weight gain, hypertension, and glucose intolerance, all factors promoting CVD. However, GCs are not ever conflicting. In RA patients with a known history of CVD, steroid therapy surprisingly attenuated the risk of CV death [145]. The mechanism of this apparent discrepancy with GC exposure is still unknown, but it seems to be related with dose, duration, and intensity of the exposure.

Although coronary artery disease and acute myocardial infarction are inflammatory disorders, the only drugs with anti-inflammatory effect so far widely used in ischemic heart disease are

The contribution of coxibs and most nonsteroidal anti-inflammatory drugs (NSAIDs) to lowering CVR is not well established and the evidence available so far is controversial. Multiple studies provide evidence that methotrexate is protective against CV events and CV mortality, although the protective benefit is under discussion [146]. Immunomodulatory or immunosuppressive therapies, such as cyclosporine and colchicine, may have benefits in coronary artery disease [147]. Other studies have found that glucocorticoids plus cytotoxic immunosuppressive agents (azathioprine, cyclosporine, and leflunomide) are associated with an increased

The new targeted biological therapies, such as the suppression of systemic inflammation by anti-TNF therapies, seem to be associated with concomitant reduction in the risk of CV events

**7. Some lessons from CVD and rheumatic-associated therapies**

mechanisms that predispose to atherothrombosis [139].

aspirin and statins (e.g., atorvastatin and simvastatin).

amount of CV events when compared with methotrexate alone [148].

136, 137].

104 An Interdisciplinary Approach to Psoriasis

Atherosclerosis is a complex disease but, as specific knowledge increases, the immune system can be clearly recognized to be involved in all steps of vascular pathology. Both classical and non-classical CVR factors are closely interconnected in the production of chronic inflammation through loss of immune homeostasis; indeed, either molecules or cells involved in atherogenesis present altered regulatory and/or effector immune functions, attenuating and promoting atherogenesis.

Some authors have proposed an autoimmune origin in atherosclerosis [82, 83]. Immune system homeostasis alterations against the patient's own antigens and the increasing prevalence of atherosclerosis in immune-mediated diseases, such as diabetes, periodontal disease, systemic sclerosis, antiphospholipid syndrome, RA, SLE, ankylosing spondylitis (AS), and PsA strongly reinforce the involvement of autoimmune mediators and the key role of inflammation in atherosclerosis [150]. This autoimmune response to oxidized LDL is a driving force for cell activation in the human atherosclerotic plaque [151]. The fact that low and high grade chronic inflammatory disorders present an accelerated progression of atherosclerosis constitutes indirect but critical evidence that strengthens the above-mentioned immune-mediated inflammation. The Ps/PsA proatherosclerotic profile seems to be related to chronic inflammation through classical and non-classical factors. Important insights reviewed in this article indicate that most, if not all inflammatory factors, are the result of immune activation and cytokine-driven inflammation.

For example, Th1, CTL, and Th17 effector cells are the dominant types in the pathogenesis of the psoriatic and cardiovascular diseases and are the most abundant T lymphocytes in skin, joints, and human atherosclerotic plaque [63]. In addition, reduced levels of circulating anti-inflammatory mediators and Treg may increase CV risk in both diseases [146, 152] inducing up-regulation of adhesion molecules [153] and promoting a more procoagulant [154] and vasoconstrictor phenotype [155]. Although anti-atherogenic humoral response could be verified, its anti-atherogenic action must be confirmed [2].

Indirect evidence indicating that immune-mediated inflammation is a key regulator in the crossroad of pathogenesis between Ps/PsA and atherogenesis derives from the role of certain therapies. Some drugs used in the treatment of CV disease, such as statins and ACE inhibitors, have anti-inflammatory activity. In addition, systemic treatments for Ps that decrease inflammation also reduce CV risk [156]. TLRs are the best candidates to explain what triggers and sustains the natural and adaptive immune response, maintaining proinflammatory cytokine gene expression in chronic inflammation, worsening atherosclerosis [145] in general population and in Ps patients.

Finally, the role of obesity, metabolic syndrome (possible via hypertriglyceridemia and associated abdominal adiposity in Ps/PsA patients), and probably DM, in this scenario of severe Ps and accelerated CVR. Adipose tissue is not just an "endocrine organ." Now, we know adipocytes express TLRs, which are involved in the innate immune response reacting to exogenous and endogenous stimuli by releasing inflammatory cytokines, adipokines, and other key mediators of Ps and atherogenesis. In addition, a consistent association was described between increasing obesity and lower serum 25-hydroxy vitamin D (25D) concentrations [147, 157].

In summary, chronic immune-mediated inflammation plays a key role in the pathogenesis of atherosclerosis in Ps, acting independently and/or synergistically with the conventional risk factors.

Framingham risk score (FRS), which only takes into account traditional CV risk factors for estimating the 10-year risk of CV events like metabolic syndrome and diabetes, may underestimate CVR related to underlying inflammatory factors associated with this disease, also known as non-traditional risk factors. Improvement by inflammatory suppression argues strongly for immune-mediated inflammation as the central risk factor for CVD in PsA. However, many of the studies investigating mechanisms of PsA associated with atherogenesis are not definitive or conclusive enough. Larger, more systematic, and controlled studies are needed to confirm many of the findings previously reviewed.

## **9. Conclusions**

Most evidence reviewed in this chapter strongly supports the hypothesis that the inflammatory immune-mediated pathogenesis is probably the mayor force beyond the atherogenesis, from its initiation to plaque formation, rupture, and associated thrombotic complications. Taken together, evidence so far strongly suggests immune-mediated inflammation is the central actor in atherogenesis beyond all risk factors, regardless of whether they are "traditional" or "non-traditional." Although certain crossroads between immune-mediated inflammation pathways are activated in general population under cardiovascular risk conditions, it seems to be potentiated in psoriasis patients and other IMID. This is in agreement with accumulated evidence so far that indicates an enhanced CVR associated with Ps via both traditional and non-traditional factors immune-modulation.

Evidence so far suggests that patients with PsA and aggressive clinical presentation of Ps should be treated more aggressively for CVR prevention and modification. Therefore, selective long-term anti-atherosclerotic immunomodulation-oriented therapy might improve atherogenesis in both general population and Ps patients.

The existence of proatherogenic immunological pathways in CID that could damage the CV system reveals potential targets for more efficient therapies. This much more selective therapy requires long-term studies until it is available and accurate enough (**Figure 2**).

**Figure 2.** Interactions between autoreactive, metabolic, and endothelial inflammation. Adipose tissue releases numerous inflammatory cytokines (TNF, IL6, resistin, leptin, and vistatin) that contribute to elevate systemic inflammatory burden. The inflammatory load is also increased by the contribution of inflammatory cytokines derived from the affected tissues derived autoimmune diseases. The total inflammatory load is increased only in these patients. These molecules perpetuate and potentiate the inflammatory process, exerting a relevant proatherogenic effect. Increased uncontrolled inflammation also leads to increased oxidative stress and prothrombotic risk. Then, burden psoriatic disease is likely to be aggravated by the concurrence of augmented inflammatory burden along with disregulated activity.

## **Abbreviations**

Indirect evidence indicating that immune-mediated inflammation is a key regulator in the crossroad of pathogenesis between Ps/PsA and atherogenesis derives from the role of certain therapies. Some drugs used in the treatment of CV disease, such as statins and ACE inhibitors, have anti-inflammatory activity. In addition, systemic treatments for Ps that decrease inflammation also reduce CV risk [156]. TLRs are the best candidates to explain what triggers and sustains the natural and adaptive immune response, maintaining proinflammatory cytokine gene expression in chronic inflammation, worsening atherosclerosis [145] in general population and in Ps patients. Finally, the role of obesity, metabolic syndrome (possible via hypertriglyceridemia and associated abdominal adiposity in Ps/PsA patients), and probably DM, in this scenario of severe Ps and accelerated CVR. Adipose tissue is not just an "endocrine organ." Now, we know adipocytes express TLRs, which are involved in the innate immune response reacting to exogenous and endogenous stimuli by releasing inflammatory cytokines, adipokines, and other key mediators of Ps and atherogenesis. In addition, a consistent association was described between increasing obesity and lower serum 25-hydroxy vitamin D (25D) concentrations [147, 157].

In summary, chronic immune-mediated inflammation plays a key role in the pathogenesis of atherosclerosis in Ps, acting independently and/or synergistically with the conventional risk factors. Framingham risk score (FRS), which only takes into account traditional CV risk factors for estimating the 10-year risk of CV events like metabolic syndrome and diabetes, may underestimate CVR related to underlying inflammatory factors associated with this disease, also known as non-traditional risk factors. Improvement by inflammatory suppression argues strongly for immune-mediated inflammation as the central risk factor for CVD in PsA. However, many of the studies investigating mechanisms of PsA associated with atherogenesis are not definitive or conclusive enough. Larger, more systematic, and controlled studies

Most evidence reviewed in this chapter strongly supports the hypothesis that the inflammatory immune-mediated pathogenesis is probably the mayor force beyond the atherogenesis, from its initiation to plaque formation, rupture, and associated thrombotic complications. Taken together, evidence so far strongly suggests immune-mediated inflammation is the central actor in atherogenesis beyond all risk factors, regardless of whether they are "traditional" or "non-traditional." Although certain crossroads between immune-mediated inflammation pathways are activated in general population under cardiovascular risk conditions, it seems to be potentiated in psoriasis patients and other IMID. This is in agreement with accumulated evidence so far that indicates an enhanced CVR associated with Ps via both traditional and

Evidence so far suggests that patients with PsA and aggressive clinical presentation of Ps should be treated more aggressively for CVR prevention and modification. Therefore, selective long-term anti-atherosclerotic immunomodulation-oriented therapy might improve ath-

are needed to confirm many of the findings previously reviewed.

non-traditional factors immune-modulation.

erogenesis in both general population and Ps patients.

**9. Conclusions**

106 An Interdisciplinary Approach to Psoriasis



## **Conflict of interest statement**

The authors have no competing interests or financial, political, personal, religious, ideological, academic, intellectual, commercial, or any other issues to declare in relation to this manuscript.

## **Author details**

Rodolfo A. Kölliker Frers1,2‡, Matilde Otero-Losada3 ‡, Eduardo Kersberg2 , Vanesa Cosentino2 and Francisco Capani1,4\*

\*Address all correspondence to: franciscocapani@hotmail.com

1 Laboratory of Cytoarchitecture and Neuronal Plasticity, Institute of Cardiological Research, University of Buenos Aires, Natl. Res. Council. ININCA.UBA.CONICET., Buenos Aires, Argentina

2 Rheumatology Department, J. M. Ramos Mejia Hospital, Buenos Aires, Argentina

3 Laboratory of HPLC, Institute of Cardiological Research, University of Buenos Aires, Natl. Res. Council. ININCA.UBA.CONICET., Buenos Aires, Argentina

4 Department of Biology, University John F. Kennedy, Buenos Aires, Argentina

‡ Rodolfo A. Kölliker Frers RA and Matilde Otero-Losada share authorship based on their participation in this work.

## **References**

**Conflict of interest statement**

HSP Heat shock protein HDL High-density lipoprotein HIF-1 Hypoxia-induced factor-1 ICAM Intercellular adhesion molecule

108 An Interdisciplinary Approach to Psoriasis

IL Interleukin

IFN-γ Interferon gamma

IMT Intima-media thickness LDL Low-density lipoprotein

MMPs Matrix metalloproteinases

MAPK Mitogen-activated protein kinases MCP-1 Monocyte chemoattractant protein 1

iNOS Inducible nitric oxide synthase

IP-10 Interferon-inducible protein 10 ICAM1 Intercellular cell-adhesion molecule 1

LFA Lymphocyte function-associated antigen-1

Rodolfo A. Kölliker Frers1,2‡, Matilde Otero-Losada3

\*Address all correspondence to: franciscocapani@hotmail.com

Res. Council. ININCA.UBA.CONICET., Buenos Aires, Argentina

**Author details**

Francisco Capani1,4\*

participation in this work.

Argentina

The authors have no competing interests or financial, political, personal, religious, ideological, academic, intellectual, commercial, or any other issues to declare in relation to this manuscript.

1 Laboratory of Cytoarchitecture and Neuronal Plasticity, Institute of Cardiological Research, University of Buenos Aires, Natl. Res. Council. ININCA.UBA.CONICET., Buenos Aires,

3 Laboratory of HPLC, Institute of Cardiological Research, University of Buenos Aires, Natl.

‡ Rodolfo A. Kölliker Frers RA and Matilde Otero-Losada share authorship based on their

2 Rheumatology Department, J. M. Ramos Mejia Hospital, Buenos Aires, Argentina

4 Department of Biology, University John F. Kennedy, Buenos Aires, Argentina

‡, Eduardo Kersberg2

, Vanesa Cosentino2 and


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