**4. Overview of skin**

192 Psoriasis

pathological factors including: growth conditions, onset of labor during pregnancy or exposure to ultraviolet irradiation (Michal et al., 2010). Of note, locally produced CRH can directly regulate steroid hormone production by adrenals and gonads. Furthermore, CRH in the immune cells can induce production and release of POMC derived ACTH and betaendorphin peptides. In vertebrates these peptides interact with membrane-bound CRH-R1 and CRH-R2 (Grammatopoulos et al., 2002) (Hillhouse et al., 2002). Both receptor types belong to the group II subfamily of G protein-coupled receptors (GPCRs). In human skin, CRH-R1 is the major receptor, expressed in both epidermal, dermal and subcutis with CRH-R1α being the most prevalent isoform. The CRH-R2 gene was expressed solely in hair follicle keratinocytes and papilla fibroblasts, whereas CRH-R2 antigen was localized predominantly in hair follicles, sebaceous and eccrine glands, muscle and blood vessels (**a**Slominski et al., 2004). A hair follicle is a typical stress-responding mini organ with a peculiar immune system. The proximal epithelium of an anagen hair follicle is known to be an area of immune privilege within the hair follicle immune system, whose collapse may be

It has been known for several decades that stress, whether inflammatory, traumatic or psychological, is associated with concurrent activation of the HPA axis. In the early 1990s, it also became apparent that cytokines and other humoral mediators of inflammation are potent activators of the central stress response, constituting the afferent limb of a feedback loop through which the immune/inflammatory system and the CNS communicate (Chrousos 1995). All three inflammatory cytokines, tumor necrosis factor-(TNF), interleukin-1β and interleukin-6 (IL-6) can cause stimulation of the HPA axis alone, or in synergy with each other (Chrousos, 1995) (Tsigos et al., 1997). There is evidence to suggest that IL-6, the main endocrine cytokine, plays the major role in the immune stimulation of the axis, especially in chronic inflammatory stress. Some of the activating effects of cytokines on the HPA axis may be exerted indirectly by stimulation of the central catecholaminergic pathways. Conversely, activation of the HPA axis has profound inhibitory effects on the inflammatory/immune response because virtually all the components of the immune response are inhibited by cortisol. Alterations of leukocyte traffic and function, decreases in production of cytokines and mediators of inflammation, and inhibition of the latter's effects on target tissues are among the main immunosuppressive effects of glucocorticoids

Studies on stress-associated immune dysregulation have interested scientists and clinicians in the field of psychoneuroimmunology (PNI). This field focuses on the interactions among the central nervous system (CNS), the endocrine system and the immune system, and the impact these interactions have on health. Modulation of the immune response by the CNS is mediated by a complex network of signals that function in bi-directional communication among the nervous, endocrine and immune systems. HPA and SAM axes are the two major pathways through which immune function can be altered. The efferent sympathetic/adrenomedullary system apparently participates in a major fashion in the

crucial for the pathogenesis of alopecia areata (Christoph et al., 2000).

**3.3 HPA axis–immune system interactions** 

(Chrousos, 1995) (Elenkov, 1999).

**3.4 HPA: The field of psychoneuroimmunology** 

#### **4.1 Skin (epidermal barrier homeostasis)**

The epidermis and its array of appendages undergo ongoing renewal by a process called homeostasis. Stem cells in the epidermis have a crucial role in maintaining tissue homeostasis by providing new cells to replace those that are constantly lost during tissue turnover or following injury (Blanpain et al., 2009). A homeostatic process involved in the maintenance of an internal steady state within a defined tissue of an organism, including control of cellular proliferation and death(apoptosis) and control of metabolic function. Mammalian epidermis is a stratified epithelium that retains the ability to self renews under both homeostatic and injury conditions by maintaining a population of mitotically active cells in the hair follicles and innermost basal layer (Niemann et al., 2002) (Ito et al., 2005). The basic mechanisms and signalling pathways that orchestrate epithelial morphogenesis in the skin have been designed for protective effect of this organ. The stratum corneum is the outermost of the 5 layers of the epidermis and is largely responsible for the vital barrier function of the skin. The physical barrier localized primarily in the stratum corneum and consists of protein-enriched cells (corneocytes with cornified envelope and cytoskeletal elements, as well as corneodesmosomes) and lipidenriched intercellular domains. The nucleated epidermis, with its tight, gap and adherens junctions, additional desmosomes and cytoskeletal elements, also contributes to the barrier. Lipids are synthesized in the keratinocytes during epidermal differentiation and are then extruded into the extracellular domains, where they form lipid-enriched extracellular layers (Jensen et al., 2009). Activation of HPA axis with release of stress neuropeptides is essential for biological homeostasis and responses to external and internal challenges (Lotti et al., 1999) (**b**Slominski et al., 1996).

#### **4.2 Skin – Neuroendocrine organ**

More than ten years ago a comprehensive model of the skin acting as neuroendocrine organ has been proposed (Milstone et al., 1988) (**a**Slominski et al., 2000). For example, the skin synthesizes vitamin D, which enters the circulation and, upon activation, exerts profound metabolic and endocrine effects (Kragballe et al., 1996). Although the concept is still evolving, it relies on the skin capacity to communicate with the central system and to regulate global homeostasis through local production and/or systemic release of classical hormones, neuropeptides, neurotransmitters and biological regulators (**b**Slominski et al., 2000).

Psoriasis and Stress – Psoriasis Aspect of Psychoneuroendocrinology 195

Fig. 2. The skin SNS are mediated via production of CRH and POMC peptides, and modulated by the local skin immune system (SIS). Signals originating in the latter and represented by proinflammatory cytokines perhaps stimulate production of CRH and POMC peptides. In turn, the signals generated by the interaction of CRH, ACTH, MSH, and

β-endorphin, with their corresponding receptors, counteract the effect of local stress

Studies have shown that stress diminishes vaccine responses, exacerbates viral and bacterial pathogenesis, slows wound healing and alters autoimmune diseases (McCabe et al., 2000) (Padgett et al., 1998) (Teunis et al., 2002) (Dowdell et al., 1999). Because lymphocytes, monocytes or macrophages and granulocytes, exhibit receptors for many neuroendocrine products of the HPA and SAM axes, such as cortisol and catecholamines, which can cause changes in cellular trafficking, proliferation, cytokine secretion, antibody production and cytolytic activity .These studies have demonstrated that stress hormones inhibit the trafficking of neutrophils, macrophages, antigen-presenting cells, natural killer (NK) cells and T and B lymphocytes, suppress the production of proinflammatory cytokines and chemokines, downregulate the production of cytokines necessary for the generation of

(Slominski et al., 2006).

**4.5 Skin – The field of psychoneuroimmunology** 

#### **4.3 Skin – Local stress (neuroendocrine activity)**

Skin as a neuroendocrine organ, is a relatively new addition to the field of cutaneous biology; it combines concepts from immunology, endocrinology, and neurobiology to unravel the multidirectional communications between brain, the endocrine and immune systems, and peripheral organs (Blalock, 1989) (Pennisi, 1997) (Turnbull et al., 1999). In this regard, the skin has a unique role because of its location, size, and relative functional diversity. Moreover, cutaneous signals sent to neuroendocrine centers may play modulatory roles, although peripheral intraorgan or inter systemic communications are also necessary to maintain global and local homeostasis. Thus precise stress-response coordination is an additional cutaneous function that appears to be served by locally expressed neuroendocrine activities (**a**Slominski et al., 2000) (**b**Slominski et al., 2000) (Slominski et al., 2001).

#### **4.4 Skin – Stress neuropeptides**

#### CRH/CRH-R1 system: Is it a cutaneous HPA system?

Slominski and colleagues have extensively documented the nature of peripheral CRH, its receptors and their distribution in human and murine skin. They confirmed that skin stress– response system was coordinated by a local cutaneous HPA axis-like system. They demonstrated that CRH, its receptors, the related neuropeptide urocortin and proopiomelanocortin-derived peptides are expressed locally in normal skin, normal cycling hair follicle epithelium, benign and malignant melanocytic lesions and non-melanoma skin cancer (**b**Slominski et al., 2004). Corresponding functional receptors (CRH-R) in the same cells confirm paracrine or autocrine modes of action. In human skin, CRH-R1 mediates most phenotypic effects of CRH (Slominski et al., 2001) while the main adnexal location of CRH-R2 indicates a role for this receptor in hair cycling (Kauser et al., 2006). Then a localized circuit regulates the peripheral functions of cutaneous CRH/CRH-R1, and the aberrant expression of CRH/CRH-R1 in the skin disturbs the local homeostasis and leads to abnormal differentiation and proliferation in keratinocytes. Because of the aberrant terminal differentiation of keratinocytes, psoriatic plaques have scale on the surface, which breaks in the protective barrier (Bowcock et al., 2005). However, dysfunction of keratinocytes may decrease CRH/CRH-R1 expression because of disharmony in differentiation and proliferation of keratinocytes. Zhou et al., in 2009 found a significant detuning CRH/CRH-R1 system in psoriatic lesions, which suggests that an aberrant cutaneous HPA system might take part in the pathogenesis of psoriasis, especially the formation of plaque. Thus, they hypothesize that a cutaneous CRH/CRH-R1 system might be aberrant in lesions of psoriasis. The detuning of CRH/CRH-R1 regulation might contribute to the formation of plaque in psoriasis (zhou et al., 2009) (Slominski et al., 2005) (Fig. 2).

POMC is a prohormone that produces various bioactive peptides via a series of enzymatic steps in a tissue-specific manner, including ACTH, α-melanocyte stimulating hormone (α-MSH), and β-endorphin. POMC is expressed not only in the pituitary gland, but also in a variety of non-pituitary organs, including the skin (Millington 2006). The production of POMC peptides in keratinocytes and melanocytes was found to be under regulatory control (Schauer et al., 1994) being stimulated by UVB, selected cytokines, and by disease processes(Slominski et al., 1996**c**, 1998, 1993**a**, 1993**b**)( Chakraborty et al., 1996) ( Winzen et al. 1996)( Wakamatsu et al., 1997).

Skin as a neuroendocrine organ, is a relatively new addition to the field of cutaneous biology; it combines concepts from immunology, endocrinology, and neurobiology to unravel the multidirectional communications between brain, the endocrine and immune systems, and peripheral organs (Blalock, 1989) (Pennisi, 1997) (Turnbull et al., 1999). In this regard, the skin has a unique role because of its location, size, and relative functional diversity. Moreover, cutaneous signals sent to neuroendocrine centers may play modulatory roles, although peripheral intraorgan or inter systemic communications are also necessary to maintain global and local homeostasis. Thus precise stress-response coordination is an additional cutaneous function that appears to be served by locally expressed neuroendocrine activities (**a**Slominski et al., 2000) (**b**Slominski et al., 2000)

Slominski and colleagues have extensively documented the nature of peripheral CRH, its receptors and their distribution in human and murine skin. They confirmed that skin stress– response system was coordinated by a local cutaneous HPA axis-like system. They demonstrated that CRH, its receptors, the related neuropeptide urocortin and proopiomelanocortin-derived peptides are expressed locally in normal skin, normal cycling hair follicle epithelium, benign and malignant melanocytic lesions and non-melanoma skin cancer (**b**Slominski et al., 2004). Corresponding functional receptors (CRH-R) in the same cells confirm paracrine or autocrine modes of action. In human skin, CRH-R1 mediates most phenotypic effects of CRH (Slominski et al., 2001) while the main adnexal location of CRH-R2 indicates a role for this receptor in hair cycling (Kauser et al., 2006). Then a localized circuit regulates the peripheral functions of cutaneous CRH/CRH-R1, and the aberrant expression of CRH/CRH-R1 in the skin disturbs the local homeostasis and leads to abnormal differentiation and proliferation in keratinocytes. Because of the aberrant terminal differentiation of keratinocytes, psoriatic plaques have scale on the surface, which breaks in the protective barrier (Bowcock et al., 2005). However, dysfunction of keratinocytes may decrease CRH/CRH-R1 expression because of disharmony in differentiation and proliferation of keratinocytes. Zhou et al., in 2009 found a significant detuning CRH/CRH-R1 system in psoriatic lesions, which suggests that an aberrant cutaneous HPA system might take part in the pathogenesis of psoriasis, especially the formation of plaque. Thus, they hypothesize that a cutaneous CRH/CRH-R1 system might be aberrant in lesions of psoriasis. The detuning of CRH/CRH-R1 regulation might contribute to the formation of

POMC is a prohormone that produces various bioactive peptides via a series of enzymatic steps in a tissue-specific manner, including ACTH, α-melanocyte stimulating hormone (α-MSH), and β-endorphin. POMC is expressed not only in the pituitary gland, but also in a variety of non-pituitary organs, including the skin (Millington 2006). The production of POMC peptides in keratinocytes and melanocytes was found to be under regulatory control (Schauer et al., 1994) being stimulated by UVB, selected cytokines, and by disease processes(Slominski et al., 1996**c**, 1998, 1993**a**, 1993**b**)( Chakraborty et al., 1996) ( Winzen et

**4.3 Skin – Local stress (neuroendocrine activity)** 

CRH/CRH-R1 system: Is it a cutaneous HPA system?

plaque in psoriasis (zhou et al., 2009) (Slominski et al., 2005) (Fig. 2).

(Slominski et al., 2001).

**4.4 Skin – Stress neuropeptides** 

al. 1996)( Wakamatsu et al., 1997).

Fig. 2. The skin SNS are mediated via production of CRH and POMC peptides, and modulated by the local skin immune system (SIS). Signals originating in the latter and represented by proinflammatory cytokines perhaps stimulate production of CRH and POMC peptides. In turn, the signals generated by the interaction of CRH, ACTH, MSH, and β-endorphin, with their corresponding receptors, counteract the effect of local stress (Slominski et al., 2006).

#### **4.5 Skin – The field of psychoneuroimmunology**

Studies have shown that stress diminishes vaccine responses, exacerbates viral and bacterial pathogenesis, slows wound healing and alters autoimmune diseases (McCabe et al., 2000) (Padgett et al., 1998) (Teunis et al., 2002) (Dowdell et al., 1999). Because lymphocytes, monocytes or macrophages and granulocytes, exhibit receptors for many neuroendocrine products of the HPA and SAM axes, such as cortisol and catecholamines, which can cause changes in cellular trafficking, proliferation, cytokine secretion, antibody production and cytolytic activity .These studies have demonstrated that stress hormones inhibit the trafficking of neutrophils, macrophages, antigen-presenting cells, natural killer (NK) cells and T and B lymphocytes, suppress the production of proinflammatory cytokines and chemokines, downregulate the production of cytokines necessary for the generation of

Psoriasis and Stress – Psoriasis Aspect of Psychoneuroendocrinology 197

which are commonly found on pathogens. In the adaptive immune system, immune cells respond to proteins and other antigens that they may never have seen before, which are presented to them by other cells. The immune cells, such as dendritic cells (Dendritic cells are present in tissues in contact with the external environment, such as the skin: Once activated, they migrate to the lymph nodes where they interact with T cells and B cells to initiate and shape the adaptive immune response) and T cells, move from the dermis to the epidermis, secreting chemical signals, such as tumor necrosis factor-α, interleukin-1β, and interleukin-6, which cause inflammation, and interleukin18, 22 which causes keratinocytes to proliferate (Banchereau et al., 1998) (Nestle et al., 2009). Recent studies indicate that various cytokines play an essential role in the induction and maintenance of psoriatic lesion.

Various inflammatory cytokines and growth factors have been shown to be strongly induced in keratinocytes in psoriatic lesion. Although it is thought that the induction of cytokine production is the consequence of the activation of infiltrating immune cells rather than a triggering factor for the inflammatory process (Lowes et al., 2007). Three types of cytokines elaborated by keratinocytes are of particular interest in this context: growth factors for keratinocytes, endothelial cells and neutrophil-attracting chemokines. Several growth factors are able to induce keratinocyte proliferation and have been found to be highly expressed in lesional psoriatic epidermis. Transforming growth factor *α* (Elder et al., 1989) (Addison et al., 2010) and amphiregulin-epidermal growth factor (Cook et al., 1992) have been shown to induce epidermal proliferation and reproduce some aspects of the psoriatic phenotype when expressed in epidermal keratinocytes in transgenic animals (Cook et al., 1999) (Vassar et al., 1991). The epidermal growth factor (EGF) receptor ligand amphiregulin (AREG) has been implicated as an important autocrine growth factor in several epithelial malignancies and in psoriasis, a hyperproliferative skin disorder. In vitro, in vivo and clinical studies are well established the role of growth factors and neuropeptides in cutaneous innervation and there is substantial evidence that sensory neuropeptides

CRH is a central component of the local HPA axis, which has a functional equivalent in the skin. The ability of CRH to activate mast cells may explain its proinflammatory actions and the pathophysiology of certain skin conditions, which are precipitated or exacerbated by stress, such as atopic dermatitis, eczema, psoriasis, and urticaria (Theoharides et al., 1998). Mast cells are derived from stem cells in the bone marrow and migrate into tissues where they are prominently located just below the dermal–epidermal junction; they mature, depending on the tissue, under the influence of stem cell factor (SCF), interleukin 3 (IL-3), IL-4 and IL-9 (Wedemeyer et al., 2000). Mast cell infiltration and/or proliferation in the skin can be triggered by SCF released from fibroblasts and other immune cells, nerve growth factor (NGF) released from nerve endings, or RANTES (regulated on activation, normal T cells, expressed and secreted) (Conti et al., 1998) . Mast cells can also secrete SCF (de Paulis et al., 1999) and NGF (Xiang et al., 2000), thus affecting their own growth and activation (Gagari et al., 1997). The cytokines expressed by mast cells are primarily pro-inflammatory or are necessary for innate immunity [e.g. IL-1, IL-6, IL-8 and

contribute to the development of psoriasis (Saraceno et al., 2006).

**5.2.3 Keratinocytes & peripheral CRH/CRH-R1** 

**5.2.2 Keratinocytes – Cytokines** 

adaptive immune responses and impair effector functions of macrophages, NK cells and lymphocytes. For example, treatment of peripheral blood leukocytes (PBLs) with catecholamines *in vitro* results in the suppression of interleukin-12 (IL-12) synthesis and an increase in IL-10 production (Elenkove et al., 1996). Data from both human and animal studies show that the connections between the neuroendocrine system and immune system provide a finely tuned regulatory system required for health. However, the immune cells and cytokines influencing keratinocyte function play a major role in the development and pathogenesis of psoriasis.
