**2. IL-23/IL-17 axis is a major immune pathway in the development of psoriasis**

#### **2.1 Psoriasis is a TH17-driven disease**

In psoriatic skin, immune response is overactive. Excess amounts of cytokines were produced, which caused prolonged inflammation and abnormal proliferation of keratinocytes. In recent decades, genetic and immunological studies have made progress in dissecting the mechanisms of psoriasis. Psoriasis was previously thought to be an interferon (IFN)-γ-producing T helper (TH) 1-driven autoimmune inflammatory disease [12, 13]. However, the discovery of TH17 cells shifted the view of psoriasis as an TH17-dependent pathology rather than TH1 cells [12–14].

IFN-γ is increased in serum from psoriasis patients and its mRNA is elevated in skin lesions [15, 16]. It was hypothesized that IFNγ blockade could decrease disease activity due to the appreciation of elevated IFN-γ expression in psoriasis. A neutralized humanized anti-IFN-γ antibody, HuZAF, was developed and tested in two small pilot studies between 2001 and 2003 [17]. In the study that was designed to determine the efficacy of miltidose HuZAF, of all 10 patients treated four times with 10 mg/kg of HuZAF, only 1 patient (10%) achieved a significant clinical response. The expression of CXCL9 was significantly suppressed by HuZAF through week 12. This finding suggests IFN-γ was successfully blocked by HuZAF in these patients since CXCL9 is heavily regulated by IFN-γ. The limited clinical efficacy of IFNγ blockade by HuZAF in patients with psoriasis suggest that infiltration of TH1 cells in psoriatic plaque likely contribute little to the pathogenesis of this disease.

The naive T cells are differentiated into TH1, TH2, TH17, or Treg cells depending on specific cytokines released by antigen-presenting cells and T-cell receptor stimulation and costimulation. The differentiation of TH17 cells are induced by interleukin (IL)-6, transforming growth factor (TGF)-β, and IL-21 [18–20]. Maintenance of TH17 population requires IL-23, a heterodimeric cytokine expressed by macrophages and dendritic cells [21, 22]. The intracellular transcription factors RORγt and STAT3 are also critical in the development of TH17 cells. Binding of IL-23 to IL-23 receptor (IL23R) attracts a heterodimer of kinase JAK2 and TYK2 and induces phosphorylation of STAT3, which enhances RORγ-mediated transcription of IL-17A and IL-17F [23, 24]. TGF-β1 is

*Developing Novel Molecular Targeted Therapeutics for Topical Treatment of Psoriasis DOI: http://dx.doi.org/10.5772/intechopen.102725*

abundantly expressed in plasma and scales from psoriatic lesions and transgenic mice that overproduce human TGF-β1 in basal keratinocytes exhibit classic signs of psoriasis [25]. Similar observations were made with STAT3, which is overproduced in psoriasis, and its transgenic mice also exhibit psoriasis-like phenotypes [26]. Under the regulation of IL-23, activated TH17 cells in the skin produce high levels of IL-17, which is often referred to as the IL-23/IL-17 axis.

#### **2.2 IL-23 stimulates TH17 cell survival and proliferation**

On developing TH17 cells, the expression of IL-23R is induced by intracellular signaling through RORγt and STAT3 and extracellular TGF-β1. The expression of IL-23R then promotes responsiveness to IL-23, which is the key cytokine in the survival and proliferation of TH17 cells [27, 28]. In psoriasis lesions, IL-23 is overproduced by dendritic cells and keratinocytes [29–31].

The importance of IL-23 in psoriasis has been confirmed by genetic studies. Polymorphisms in both subunits of IL-23, IL23A (p19) and IL12B (p40), and IL23R have been reported to be associated with an increased risk of psoriasis in North Americans, Europeans and Asians [32, 33]. A common risk haplotype of IL-23R, proline at amino acid 310 and arginine at amino acid 381, was identified. A single amino acid change from arginine to glutamine at amino acid 381 in IL-23R was found to be protective against psoriasis. Interestingly, this amino acid is located at the JAK2 kinase-binding domain of IL-23R. It is likely the change to glutamine breaks the IL-23R signaling and blocks inflammatory response induced by TH17 cell. In mouse studies, intradermal injection of recombinant IL-23 in normal-appearing skin induces skin inflammation and produces erythematous, thick and scaly skin with histologic features reminiscent of psoriasis [34], and IL-23 deficient mice were resistant to imiquimod-induced psoriasis-like inflammation [35]. Similarly, mice lacking IL-23 are resistant to experimental autoimmune encephalomyelitis (EAE) [21].

IL-23 belongs to the IL-12 family of cytokines and consists of two subunits: p19 and p40. P19 is unique for IL-23 and p40 is shared with IL-12. There are several lines of evidence to demonstrate the central role of IL-23, but not IL-12, in the pathogenesis of psoriasis [14]. The high expression of p19 and p40, but not IL-12 specific p35 expression, was observed in psoriatic lesions as compared to nonlesional skin [36]. Mice lacking the p35 subunit of IL-12 (*Il12a*−/−) or the IL-12-respectific receptor subunit (*Il12rb2*−/−) significantly increased skin inflammation, consistent with the observation in the EAE model of multiple sclerosis that IL-12 knockout mice led to worsening inflammation [21, 37]. In transgenic mice, overexpression of individual subunits of IL-23 leads to inflammation [38, 39]. Ubiquitous transgenic expression of the IL-23 subunit p19 induced a striking phenotype characterized by multiorgan inflammation, runting, infertility and death before 3 month of age [38]. Furthermore, p40 transgenic mice constitutively produce IL-23 (p19/p40), but not IL-12 (p35/p40), in basal keratinocytes by secretion of transgenic p40 with endogenous p19 [39]. p40 transgenic mice cause an inflammatory skin disease, similar to that of intradermal injection of recombinant IL-23 in mice, confirming the provital role of IL-23, but not IL-12, in psoriasis pathogenesis.

#### **2.3 IL-17 is a central proinflammatory effector cytokine in psoriasis**

IL-23 is required for autoimmune inflammation mediated by TH17 cells and produces large amounts of IL-17 *in vivo* [40]. IL-23 injection into skin of wild-type mice induces psoriasis-like symptoms, but not in IL-17 knockout mice, and if the wild-type mice are pre-treated with IL-17 antibody, IL-23-induced disease is blocked, suggesting that IL-17 is downstream of IL-23 and critical role in psoriasis pathogenesis [12].

Among six isoforms of IL-17, IL-17A and IL-17F are the most pathogenic in psoriasis [31]. IL-17A is often referred to as IL-17, for which the TH17 cell lineage is named. Besides TH17 cells, a large number of other skin cells also produce IL-17, including γδ T cells, αβ T cells, neutrophils, mast cells, ILC3s and Tc17 cells. Some production is independent of IL-23 [12]. In psoriatic skin, IL-17 expression is higher, and the number of TH17 cells, γδ T cells, Tc17 cells were all greatly increased compared to normal skin [30, 41]. Genes that are up-regulated in keratinocytes treated by IL-17A *in vitro*, are corresponded to the genes up-regulated in psoriasis lesions, and the overlap is bigger than that by TNF-α or IFN-γ [42]. In response to IL-17, keratinocytes produce a variety of antimicrobial peptides (AMPs) and chemokines. They induce flammation and neutrophil recruitment and lead to hyperproliferation of the epidermis and aberrant differentiation of keratinocytes [43].

Even in nonlesional skin from psoriasis patients, expression of IL-17-downstream genes is higher compared to normal skin, and disease severity is significantly correlated with levels of IL-17 and TNF-α in blood. There is also a strong correlation between PASI scores and pathways related to IL-17 [44]. All the evidence suggests that IL-17 is the central effector cytokine in psoriasis.
