Epidermal IL-33 drives inflammation in necroptosis-induced skin inflammation by recruiting TNF-producing immune cells.
Fernandez-Nasarre, A.; Srivastava, V.; Bennett, F.; Michel, L.; Bensussan, A.; Choy, E. H.; Bagot, M.; Bonnet, M. C.
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Caspase-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 of Il-33 or St2 dramatically delays lesion development and improves survival of caspase-8EKO animals. IL-33 is highly expressed in necroptotic epidermis of caspase-8EKO mice 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.
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