## 3 Expression and Role of IL-36 Cytokines in Inflamed Skin and Joints
### Expression and Role in The inflamed Skin  
IL-36 and IL-36 Ra are physiologically present in the skin, but their expression is enhanced in psoriasis [34]. They are mainly produced by keratinocytes but also by macrophages or dendritic cells [35; 36], and their release is upregulated in vitro by various stimuli like proinflammatory cytokines or TLR agonists (e.g., lipopolysaccharide, double-stranded (ds) RNA) [37; 38; 39; 40]. In both human and murine psoriatic skin samples IL-36\(\alpha\), \(\beta\), \(\gamma\), IL-36 Ra, and IL-38 are constitutively detectable but only IL-36\(\alpha\), \(\gamma\), and IL-36 Ra are selectively further induced during active inflammation [40]. IL-36 cytokines are also upregulated in anti-TNF-induced psoriasisform lesions in patients with [PERSON]'s disease [41], and might be involved in the pathogenesis of allergic dermatitis [42], alopecia [43] and Kindler syndrome [44]. Soriatic skin lesions are characterized by hyperproliferation and altered differentiation of keratinocytes. Consequently, the release of proinflammatory mediators acting on immune cells sustains a self-amplifying loop able to perpetuate the cutaneous inflammatory process [45]. In this context, IL-36 cytokines, in cooperation with IL-17, negatively regulate keratinocytes differentiation and induce their proinflammatory phenotype [46; 47] and the development of skin lesions. IL-36 plays an important role also directly on myeloid immune cells. Upon IL-36 stimulation, dendritic cells overexpress specific activation markers such as cluster of differentiation (CD)80, CD86, or class I major histocompatibility complex (MHC) and produce IL-1\(\beta\), IL-12, IL-23, IL-6, and TNF\(\alpha\) but also chemokine (C-C motif) ligand 1 (CCL1), chemokine (C-X-C motif) ligand 1 (CXCL1), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in an IL-36R-dependent manner [48; 49]. Langerhans cells and M2 macrophages (i.e., alternatively-induced macrophages) are similarly prompted by IL-36 to increase their proinflammatory activity [50]. IL-36R is expressed by CD4/CD8 T cells and B cells. Unlike other receptors of the IL-1 family that are mostly detected on polarized T cells (e.g., IL-1R), IL-36R is primarily found on the surface of naive CD4 T lymphocytes, suggesting that IL-36 plays a role in initiating the immune response. The ability of IL-36 to regulate T cells biologic activity is of fundamental importance in psoriasis since this disease has been traditionally considered to have a T cell-mediated pathogenesis [51]. Several studies have demonstrated that IL-36 is involved in the maturation of T cells by increasing CD4 T cells proliferation [52], inducing T helper (Th) 1 polarization of Th0 cells [53], and directly triggering IL-17 production by murine CD4 T cells [35]. IL-36\(\gamma\) is also able to activate endothelial cells and promote leukocyte recruitment during skin inflammation through the induction of the expression of adhesion molecules vascular cell adhesion protein (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 [54]. Concerning the regulation of the IL-36 family members by other cytokines, it seems that IL-22 and the Th17-related cytokines enhance the IL-36 expression within psoriatic lesions in murine models and human tissues [37], thus sustaining an autocrine and paracrine amplification loop between IL-36 and Th17 cytokines [37; 47]. Interestingly, the anti-inflammatory effects of corticosteroids (e.g., dexamethasone) in mouse psoriatic skin are also driven by the disruption of the positive feedback loop between IL-36 and the Th17 axis [55]. Furthermore, the IL-36 Ra deficiency exacerbates psoriasis in animal models [35] and the Deficiency of the interleukin-36 receptor antagonist (DITRA) is a recognized human syndrome characterized by generalized pustular psoriasis [56]. Some genetic polymorphisms in the IL-36\(\beta\) locus are also known to be associated with a higher susceptibility to psoriatic arthritis [57]. In mice, IL-36\(\alpha\) is essential for the development of psoriasis.