Targeting IL-36 in Inflammatory Skin Diseases

Interleukin (IL)-36 cytokines are members of the IL-1 superfamily of cytokines. IL-36 cytokines are composed of three agonists (IL-36α, IL-36β, and IL-36γ) and two antagonists (IL-36 receptor antagonist [IL36Ra] and IL-38). These work in innate and acquired immunity and are known to contribute to host defense and to the pathogenesis of autoinflammatory diseases, autoimmune diseases, and infectious diseases. In the skin, IL-36α and IL-36γ are mainly expressed by keratinocytes in the epidermis, although they are also produced by dendritic cells, macrophages, endothelial cells, and dermal fibroblasts. IL-36 cytokines participate in the first-line defense of the skin against various exogenous assaults. IL-36 cytokines play significant roles in the host defense system and in the regulation of inflammatory pathways in the skin, collaborating with other cytokines/chemokines and immune-related molecules. Thus, numerous studies have shown IL-36 cytokines to play important roles in the pathogenesis of various skin diseases. In this context, the clinical efficacy and safety profiles of anti-IL-36 agents such as spesolimab and imsidolimab have been evaluated in patients with generalized pustular psoriasis, palmoplantar pustulosis, hidradenitis suppurativa, acne/acneiform eruptions, ichthyoses, and atopic dermatitis. This article comprehensively summarizes the roles played by IL-36 cytokines in the pathogenesis and pathophysiology of various skin diseases and summarizes the current state of research on therapeutic agents that target IL-36 cytokine pathways.