# The Significance of IL-36 Hyperactivation and IL-36R Targeting in Soriasis
## 2 Structural and Functional Characterization of II-36 Receptor  
### Organization of IL-36R Molecular Complex  
Members of the IL-36 cytokine family were originally discovered due to their homology with two members of IL-1 family IL-1\(\alpha\) and IL-1\(\beta\). Following in vitro functional characterization and identification of their cognate receptor IL-36R, the IL-36 subfamily of cytokines was re-classified as three agonist cytokines IL-36\(\alpha\), IL-36\(\beta\), and IL-36\(\gamma\) (previously termed IL-1F6, IL-1F8, and IL-1F9) and the natural antagonists IL-36 Ra and IL-38, formerly known as IL-1F5 and IL-1F10, respectively [30]. Figure 1: IL-36 circuits are hyperactivated in both acute and chronic phase of psoriasis. (**A**) Early events in psoriasis include induction of innate immunity pathways. During this phase, keratinocytes produce antimicrobial peptides, in particular the cathelecidin LL37. The latter activates pDC and mDC, which trigger, via IFN-\(\alpha\) and IL-23/IL12, the T helper (Th)17/Th22 and Th1 responses, thus initiating the adaptive immune phase. In both acute and chronic psoriasis, the expression of IL-36 cytokines is strongly upregulated by stimuli typical of innate or adaptive immunity, respectively. IL-36\(\gamma\), for instance, can be induced, together with the other IL-36 family members and IL-36 Ra, by LL37 and TNF-\(\alpha\), as well as by IL-17 and IL-22. Contrarily, inflammatory cytokines down-regulate the expression of IL-38 in skin lesions. IL-36s activate pathogenic pathways in different cell types in psoriatic skin, especially in resident skin cells, such as keratinocytes and endothelial cells (EC). In keratinocytes, IL-36s promote the release of inflammatory molecules and interferes with differentiation/comification processes of the epidermis. IL-36s also regulates the production of IL-23 and IL-12 by mDC and macrophages, thus influencing the driving of Th17 and Th1 responses in psoriatic skin. IL-36 cytokines also sustain the recruitment of neutrophils (PMN) in psoriatic skin. T-cell infiltrate present during late/chronic phase of psoriasis establishes a cytokine milieu, that further upregulate the keratinocyte production of IL-36. (**B**) Both acute and chronic phases of psoriasis can be found within the same psoriatic plaque, being it comprehensive of nonlesional proximal to perilesional and lesional areas, with IL-36\(\gamma\) expression predominantly present in the epidermis of lesional skin. IL-36 cytokines, such as all the IL-1 family members except for IL-1 Ra, are synthesized without a signal peptide and therefore are not secreted via the endoplasmic reticulum-Golgi pathway and the mechanism of their release remains yet undefined [31]. Post-translational processing is required for full agonist or antagonist activity of all IL-36 members [5; 32]. Similarly, recent in vitro and in vivo studies demonstrated that N-terminally truncated fragments of IL-38 (20-152 and 7-152 amino acid fragments) have increased biological activity compared to full-length form [33; 34]. Neutrophil-derived proteases seem to be responsible for IL-36 agonists maturation [32; 35]. However, it is unclear whether truncation of IL-36 agonists and antagonists occurs in humans under pathologic conditions. Mechanistically, IL-36 agonists bind the same heterodimeric receptor complex, composed of IL-36R (initially termed IL-1R-related protein 2 also known as IL-1 RL2 or IL-1 Rrp2) and a co-receptor subunit IL-1 receptor accessory protein, IL-1 RAcP1, which is shared by IL-1\(\alpha\), IL-1\(\beta\) and IL-33 [36] (Figure 2). IL-1 Rrp2 contains a signaling peptide, an extracellular domain (ECD), a transmembrane helix and an intracellular Toll/IL-1 receptor (TIR) domain. The protein is localized to the plasma membrane as a single-pass transmembrane protein with the ECD on the cell surface and the TIR domain localized in the cytoplasm [36]. Although the crystal structure of IL-36\(\gamma\) has been resolved, the structure of IL-1 Rrp2 or IL-1 Rrp2/IL-1 RAcP/ligand complex is not yet available.