Abstract
Psoriasis is an immune-mediated inflammatory skin disease that involves mainly T helper (Th)17, Th1 and Th22 lymphocytes, which cause hyper-proliferation of the epidermis with aberrant differentiation of keratinocytes, and local production of chemokines and cytokines. These fuel a self-amplifying loop where these products act on T cells to perpetuate cutaneous inflammatory processes. Among the various inflammatory mediators involved, interleukin (IL)-36 cytokines are important for the recruitment and activation of neutrophils and Th17 cells in psoriatic skin. In particular, IL-36s induce chemokines and cytokines interfere with differentiation/cornification programs in the epidermis, as well as promote pathological angiogenesis and endothelial cell activation. IL-36 cytokines belong to the IL-1 family, and comprise IL-36α, IL-36β, and IL-36γ agonists as well as IL-36 receptor antagonist and IL-38 antagonists. IL-36 cytokines are up-regulated in psoriatic epidermis, and their expression is strongly induced by TNF-α and IL-17. Contrarily, IL-38 antagonist is downregulated, and its impaired expression may be relevant to the dysregulated inflammatory processes induced by IL-36. Here, we discuss on the pathogenic mechanisms leading to the altered balance of IL-36 agonists/antagonists and the significance of this dysregulation in psoriasis. Collection of the information will provide a theoretical basis for the development of novel therapeutic strategies based on IL-36 agonist/antagonist manipulation in psoriasis.
Highlights
Psoriasis is a complex skin disease with autoimmune components that involves resident skin cells and immune cells, generating self-sustaining inflammatory cycles
Among keratinocyte-derived antimicrobial peptides (AMP), the catheledicin LL37 has a pivotal role in the development of psoriasis, through its capacity to activate plasmacytoid dendritic cells (pDC) and myeloid DC, 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-γ/TNF-α axes [2]
We demonstrated that IL-36R blockade by a recombinant full-length form of IL-38 restores keratinocyte differentiation impaired by IL-36γ, to what was observed with IL-36Ra, by rescuing the physiological levels of differentiation markers [13]
Summary
Psoriasis is a complex skin disease with autoimmune components that involves resident skin cells and immune cells, generating self-sustaining inflammatory cycles. Upstream events occurring in psoriasis include the induction of innate immunity pathways and responses in keratinocytes [3] (Figure 1). 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-36R-mediated signal transduction has been shown to induce a number of pathogenic pathways in different cell types of psoriatic skin, especially in resident skin cells such as keratinocytes and endothelial cells (Figure 1). We illustrate the multiple pathogenic effects of IL-36 cytokines on inflammatory responses of resident skin cells and immune cells, as well as their impact on differentiation/cornification processes of the epidermis. Collection of the information will provide a theoretical basis for the development of new therapeutic strategies for psoriasis based on IL36R-targeting
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