# Exploring the Role of IL-36 Cytokines as a New Target in Psoriatic Disease
## 2 The Role of IL-36 Family Cytokines in Psoriasis Pathogenesis
Cytokines secreted by infiltrating Th1 and Th17 lymphocytes further potentiate this inflammatory loop by inducing expression of IL-36 and other pro-inflammatory mediators such as TNF-\(\alpha\), IL-6, and CXCL8 by KCs [39] (Figure 2). IL-36-driven inflammation is mainly orchestrated by KCs, as demonstrated recently by [PERSON] and colleagues [40]. These authors found that targeted deletion of IL-36R in KCs resulted in similar levels of protection from psoriasisiform inflammation as those observed in IL-36R-deficient mice. IL-36R-deficient mice KCs also featured significantly decreased expression of IL-17A, IL-23, and IL-22, as well as loss of chemokine-induced infiltration of the inflamed skin by neutrophils and IL-17A--expressing \(\gamma\delta\) T-cell subsets [40]. These data suggest that IL-36-derived signaling in KCs play an early role in the initiation and self-amplification of the \"feed-forward\" model of psoriatic inflammation through directly regulating IL-17A expression [40]. IL-36 cytokines also enhance psoriatic skin inflammation by activating angiogenesis and promoting leukocyte recruitment. IL-36\(\alpha\) and IL-36\(\gamma\) induce KCs expression and the release of proliferative factors--such as heparin-binding EGF-like growth factor (HB-EGF) and vascular endothelial growth factor (VEGF)-A--acting on fibroblasts and endothelial cells [28]. In addition, dermal endothelial cells activated by IL-36\(\gamma\) show increased re  
Figure 2: IL-36 autocrine and autoimmunity circuits. IL-1, TNF, and IL-17A induce IL-36 expression by KCs. IL-36 cytokines are secreted as precursors that require processing by neutrophil-derived proteases (elastase, cathepsin G, or protease 3) and KC-derived cathepsin S. Mature IL-36 cytokines bind to IL-36R on the KC cell surface, acting in an autocrine manner to further induce IL-36 expression. Moreover, they promote the production and release of pro-inflammatory cytokines (IL-1\(\beta\), IL-12, IL-23, IL-6, and TNF-\(\alpha\)), neutrophil chemokines (CXCL1, CXCL2, CXCL6, and CXCL8 [(IL-8)], lymphokines (such as CCL20, CCL3) and co-stimulatory molecules by DCs and Th1. They also induce T-cell proliferation, and cytokines secreted by infiltrating Th1 and Th17 lymphocytes further potentiate this inflammatory loop by inducing IL-36 expression and other pro-inflammatory mediator production by KCs. Mon: monocytes; pDC: plasmatic dendritic cell; TIR: Toll/interleukin-1 receptor. lease of IL-6, CXCL8, CCL20, and CXCL1, increased expression of adhesion molecules, and increased proliferation and branching [28, 41]. Other immune cells expressing the IL-36 receptor, such as macrophages, LCs, and DCs, are also activated by IL-36 cytokines. IL-36\(\gamma\)-stimulated macrophages produce high levels of IL-23 and TNF\(\alpha\), activating endothelial cells and leading to increased adherence of monocytes. In turn, monocytes increase the release of IL-23, promoting the polarization of IL-17/IL-22-expressing lymphocytes [41]. In addition, anti-inflammatory M2 macrophages are driven to a pro-inflammatory M1 phenotype [36]. High levels of IL-36R mRNA have been found in LCs and dermal CD1a DCs. IL-36 cytokines potentiate Toll-like-receptor (TLR)-9 activation and IFN\(\alpha\) production, contributing to extractaneous inflammation in psoriasis [42] They are also quintessential in eliciting generalized, acute response inflammation. Last, although neutrophils do not express IL-36R, IL-36 cytokines indirectly contribute to their activation by inducing the release of neutrophil chemoattractants by KCs, as previously noted. NETs are released by neutrophils in a process called NETosis, with three possible models: (a) suicidal NETosis--dependent on production of reactive oxygen species (ROS) via the Mitogen-Activated Protein kinases (MEK)-extracellular signal-regulated kinases (ERK) signaling pathway, (b) TLR and complement receptor for C3 protein-related NETosis, and (c) mitochondrial ROS production-dependent NETosis.