# The Significance of IL-36 Hyperactivation and IL-36R Targeting in Soriasis
## 1 Introduction  
Soriasis is a complex skin disease with autoimmune components that involves resident skin cells and immune cells, generating self-sustaining inflammatory cycles. Psoriatic lesions manifest as hyperkeratotic plaques and are caused by the infiltration of effector leukocytes which induce hyperproliferation of the epidermis with aberrant differentiation of keratinocytes, dermo-epidermal inflammation, and angiogenesis [1; 2]. Early upstream events occurring in psoriasis include the induction of innate immunity pathways and responses in keratinocytes [3] (Figure 1). In this phase, keratinocytes overproduce antimicrobial peptides (AMP), cytokines of IL-1 family, and chemoattractants, altogether important for the activation and recruitment of innate immunity cells such as plasmacytoid dendritic cells (pDC), neutrophils, and macrophages [4; 5]. Among keratinocyte-derived AMP, the catheledicin LL37 has a pivotal role in the development of psoriasis, through its capacity to activate pDC and myeloid DC (mDC), with consequent initiation of the adaptive immune phase [6; 7] and activation of the IL-23-T helper (Th)17/Th22 and IL-12-IFN-\(\gamma\)/TNF-\(\alpha\) axes [2]. While IL-17/IL-22-producing T cells aremainly found in the initial phases of psoriasis, IFN-\(\gamma\)-producing Th1 and Tc1 cells accumulate during the chronic phase of the disease. Hence, T-cell infiltrate in active psoriatic skin establishes a cytokine milieu that concurs to derange proliferative and differentiation programs of the epidermis, and induce the local overexpression of several mediators of inflammation [8; 9]. An unceasing self-amplifying loop sustained by keratinocytes and adaptive immunity cells further intensifies inflammation and leads to disease perpetuation and maintenance (Figure 1). Among the variety of pathogenic mechanisms operating in psoriasis, those mediated by IL-36 cytokines have been put forward as very relevant [10; 11; 12]. IL-36 cytokines are a subgroup of the wider IL-1 family, comprising three agonists, IL-36\(\alpha\), IL-36\(\beta\), and IL-36\(\gamma\), and two antagonists, IL-36 receptor antagonist (known as IL-36 Ra or IL-36 RN) and IL-38, with opposite functions and competitively binding to IL-36R/IL-1R/AcP complex. While IL-36\(\alpha\), IL-36\(\beta\), and their antagonists, in particular IL-38, are physiologically present in healthy skin, with a prominent localization in the epidermal compartment, IL-36\(\gamma\) can be significantly detected only in psoriatic lesions. Here, IL-36 cytokines, in particular IL-36\(\alpha\), IL-36\(\gamma\) and IL-36 Ra, are highly produced by epidermal keratinocytes, and at lower extent, by dermal fibroblasts and endothelial cells (Table 1). Concomitantly, IL-38 expression is downregulated in the epidermis of psoriatic lesions [13] (Table 1). IL-36 cytokines, mostly IL-36\(\alpha\) and \(\gamma\), are also produced by macrophages, Langerhans cells, and dendritic cells infiltrating dermis of psoriatic skin [14] (Table 1). The significance of IL-36 in psoriatic inflammation has been [15; 16; 17]. IL-36 cytokine upregulation in psoriasis occurs both in the early and in the late phases of the disease (Figure 1). In both phases, IL-36 expression is induced and sustained by stimuli typical of innate or adaptive immunity, characterizing acute and chronic skin lesions, respectively. IL-36\(\gamma\), together with other IL-36 family members and IL-36 Ra, can be, in fact, strongly induced by LL37, TNF-\(\alpha\), and IL-36 themselves, as well as by IL-17 and IL-22, which accumulate in acute skin lesions [18]. Contrarily, the expression of IL-38 antagonist is down-regulated by inflammatory cytokines, and in particular by IFN-\(\gamma\), abundantly present in chronic plaques. Therefore, the unbalanced expression levels of IL-36/IL-38 may be responsible for the dysregulated inflammatory processes induced by IL-36 in psoriatic skin, especially in the epidermal compartment [13].