# The Significance of IL-36 Hyperactivation and IL-36R Targeting in Soriasis
## 3 IL36R-Dependent Responses in Seriatric Resident Skin Cells  
### Epidermal Keratinocytes  
Several findings indicate that IL-36 is involved in skin inflammation, acting mainly on epidermal keratinocytes [47; 48]. IL-36 agonists, as well as IL-36 Ra, are released by keratinocytes upon stimulation with TLR agonists (lipopolysaccharide, poli I:C) or IL-1\(\alpha\), as well as by the inflammatory cytokines TNF-\(\alpha\), IL-17 and IL-22, which accumulate in the initial phases of disease. IL-36s are able to induce its own expression by acting in an autocrine loop [18; 49]. Recently, it has been demonstrated that IL-36\(\gamma\) is also induced in epidermal keratinocytes by the neutrophil extracellular traps (NETs), large neutrophil-derived structures that contribute to the early psoriatic inflammation [50]. Contrarily, IL-38 expression is down-regulated by IL-22, IL-36\(\gamma\) and, interestingly, by Th1-released IFN-\(\gamma\), thus contributing to the unbalance of the IL-36/IL-38 ratio also in the chronic skin lesions. In fact, although IL-36 Ra antagonist is induced by inflammatory cytokines, its levels could be not sufficient to unleash the IL-36-dependent responses.  
Other than releasing IL-36s, human keratinocytes vividly respond to them by producing several pro-inflammatory mediators, such as anti-microbial peptides, including AMP, LL-37, human \(\beta\)-defensin (HBD)-2, and S100 calcium-binding protein A7 (S100A7), the cytokines TNF-\(\alpha\) and IL-6, and the neutrophil chemoattractant molecules CXCL8, CXCL1, CCL3, and CCL20, which act on immune cells, sustaining a self-amplifying inflammatory loop [18; 20]. Furthermore, IL-36\(\alpha\) and IL-36\(\gamma\) induce the expression and release of Heparin-binding EGF-like growth factor (HB-EGF) and, at lower extent, of vascular endothelial growth factor (VEGF)-A, two pro-proliferative factors acting on fibroblasts and endothelial cells, respectively [13; 19]. Additionally, in human keratinocytes, IL-36\(\gamma\), in synergy with TLR4 agonists, induces the release of lipocalin 2 (LCN2), further increasing neutrophil infiltration into the skin, and thereby amplifying the inflammatory cascade [50]. Interestingly, IL-36s strongly cooperate with IL-17A in inducing anti-microbial peptides, in particular HBD-2 and S100A7A, as well as pro-inflammatory cytokines, such as IL-6 and CXCL8, thus amplifying Th17 inflammatory responses [51].  
Other than inducing inflammation, IL-36 cytokines, alone or in synergy with IL-17A, interfere with keratinocyte differentiation. In particular, N-terminally truncated forms of IL-36\(\alpha\), \(\beta\) and \(\gamma\) cytokines downregulate the expression of various epidermal differentiation markers, including filaggrin, involucrin, keratin 1 and keratin 10, in both keratinocyte cultures undergone terminal differentiation and skin equivalent models [13; 52]. However, further studies are needed to delineate the molecular mechanisms triggered by IL-36s counteracting differentiation process in the skin. Interestingly, we demonstrated that IL-36R blockade by a recombinant full-length form of IL-38 restores keratinocyte differentiation impaired by IL-36\(\gamma\), similarly to what was observed with IL-36 Ra, by rescuing the physiological levels of differentiation markers [13]. Finally, exogenous IL-38 also suppresses the expression of pro-inflammatory molecules in human keratinocytes activated by IL-36\(\gamma\), including IL-6, CXCL8, CCL20, and the antimicrobial peptides LL-37 and HBD-2 [13].