Epidermal IL-33 drives inflammation in necroptosis-induced skin inflammation by recruiting TNF-producing immune cells

Abstract

AbstractCaspase-8 deficiency in the epidermis (caspase-8EKO) results in cutaneous inflammation resembling pustular psoriasis, triggered by necroptotic cell death of keratinocytes. Necroptosis is a highly proinflammatory form of programmed necrosis due to the release of intracellular molecules called alarmins, which can act as inflammatory mediators. However, their role in necroptosis-induced skin inflammation remains unexplored. Here, we demonstrate that alarmin IL-33 and its receptor ST2 are essential early mediators of necroptosis-induced skin inflammation. Genetic ablation ofIl-33orSt2dramatically delays lesion development and improves survival of caspase-8EKOanimals. IL-33 is highly expressed in necroptotic epidermis of caspase-8EKOmice and induces immune cell recruitment in the skin upon keratinocyte necroptosis. Impairment of the IL33-ST2 axis does not affect epidermal necroptosis but reduces the recruitment of TNF-producing infiltrating immune cells and subsequent amplification of cutaneous inflammation. Collectively, our findings highlight a pivotal role for IL-33 and ST2 in necroptosis-induced skin inflammation.TeaserInhibition of IL-33/ST2 axis alleviates necroptosis-induced skin inflammation by reducing TNF production in the dermis.