IL-36 activity during skin infections

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SUMMARY Interleukin-36 (IL-36) represents IL-36a, IL-36b and IL-36g, which are related to IL-1a and IL-1b. The IL-36 cytokines are increasingly being linked to inflammatory conditions due to elevated expression in affected tissues; however, our understanding of how these cytokines are activated and inactivated remain limited. This knowledge gap hinders informed decision making when starting clinical trials involving IL-36 receptor neutralizing antibodies and the development of cheaper small molecule drugs. We have extensively studied how the IL-36s and IL-1s promote inflammation and immunity during infections and chronic diseases. For example, we showed how they regulate protective immunity through modulation of interferon responses and recruit immune cells to the epidermis in the skin through induction of cytokines and their receptors. These studies involved models of atopic dermatitis, psoriasis, and herpes simplex virus-1 and Staphylococcus aureus infections. Pursuing new directions, we will here examine activation and inactivation mechanisms. Thus, this project will improve our understanding of IL-36 functions. The gained insight will help guide clinical trials aimed at neutralizing IL-36 and set the stage for targeted approaches involving small molecules.