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bioRxiv · 10.1101/2023.07.28.550963

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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Abstract

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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Fernandez-Nasarre, A., Srivastava, V., Bennett, F., Michel, L., Bensussan, A., Choy, E. H., Bagot, M., Bonnet, M. C.. 2023-07-29. Epidermal IL-33 drives inflammation in necroptosis-induced skin inflammation by recruiting TNF-producing immune cells.. https://doi.org/10.1101/2023.07.28.550963

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