# 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  
IL-36 cytokines belong to the IL-1 family and play an important role in the maintenance of endogenous homeostasis. They act as regulators of the innate immune system, and their uncontrolled activation and expression results in pathologic inflammatory responses, including psoriasis [24]. IL-36 cytokines are expressed in epithelial and immune cells and comprise three agonists with pro-inflammatory functions (IL-36\(\alpha\), IL-36\(\beta\), and IL-36\(\gamma\)) and two antagonists (IL-36 RN or IL-36 Ra and IL-38); all of them use the same receptor complex IL-36R [25] (Figure 1). IL-36\(\alpha\) and IL-36\(\beta\) are normally present in healthy skin, whereas IL-36\(\gamma\) is present at high levels in psoriasis lesions [25]. In the skin, IL-36\(\alpha\) and IL-36\(\gamma\) are predominantly produced by epidermal keratinocytes (KCs) but also by dermal fibroblasts, endothelial cells, macrophages, Langerhans cells (LCs), and dendritic cells (DCs) [25]. KCs are the main producers of IL-1 Ra and IL-38 in resident skin cells [24]. Overexpression of IL-36\(\alpha\), IL-36\(\beta\), and IL-36\(\gamma\) has been found in the skin and serum of psoriasis patients with a positive correlation between disease severity and cytokine levels [26; 27]. Furthermore, IL-38 levels are reduced in psoriasis patients, highlighting the unbalance of IL-36 axis in favor of pro-inflammatory IL-36 agonists [28]. IL-36 cytokines are released as precursors and require N-terminal truncation to acquire their full pro-inflammatory activity, but--unlike other IL-1 cytokines--they do not contain a caspase cleavage site [29]. Processing and activation are produced by proteases: cathepsin G, proteinase 3, and elastase (neutrophil-derived), and cathepsin S (derived from KCs and fibroblasts) [30; 31; 32; 33; 34]. Neutrophil-derived proteases are found in neutrophil extracellular traps (NETs) resulting from the programmed death of neutrophils [32]. Pro-tease inhibitors secreted by KCs can regulate the IL-36-mediated inflammatory cascade. Alpha-1-antitrypsin and alpha-1-antichymotrypsin, codified by SERPINA1 and SERPINA3 genes, inhibit the processing of IL-36 cytokines by neutrophil elastase and cathepsin G, respectively [5]. Upon binding to their receptor, IL-36 cytokines induce the activation of nuclear factor-\(\kappa\beta\) (NF-\(\kappa\beta\)) and mitogen-activated protein kinases, leading to the promotion of pro-inflammatory responses in KCs, fibroblasts, dermal endothelial cells, macrophages,  
Figure 1: Receptor and signaling pathways involved in the IL-36 axis. IL-36R is a heterodimeric complex composed of an IL-1 RL2 subunit and IL-1 RAcP co-receptor. Agonist binding (IL-36\(\alpha\), IL-36\(\beta\) or IL-36\(\gamma\)) to IL-1 RL2 results in IL-1 RAcP recruitment and the activation of intracellular pathways. The MyD88/IRAK1/IRAK2/TRAF6 platform with corresponding intracellular signaling results in pro-inflammatory gene expression. Antagonism by IL-36 Ra and IL-38 inhibits IL-36R signaling (shown in red). TIR: Toll/interleukin-1 receptor; MyD88: Myeloid differentiation primary response (88); NF-kB: nuclear factor kB; IRAK: Interleukin 1 receptor-associated kinase; TRAF: TNF receptor-associated factor; STAT3: Signal transducer and activator of transcription 3. DCs, and various T cell subsets [35]. Activated IL-36 cytokines induce the expression of pro-inflammatory cytokines, chemokines, and co-stimulatory molecules cells--such as IL-1\(\beta\), IL-12, IL-23, IL-6, and TNF-\(\alpha\), CCL1, CXCL1, and GM-CSF--by DCs and Th1 lymphocytes [36]. They also induce T-cell proliferation, with further potentiation of the inflammatory response, and signal to KCs in an autocrine manner, stimulating the additional production of pro-inflammatory cytokines, antimicrobial peptides, and neutrophil chemokines (CXCL1, CXCL2, and CXCL8) [37; 38].