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

Fernandez-Nasarre, Africa, Srivastava, Vikas, Bennett, Ffion, Michel, Laurence, Bensussan, Armand, Choy, Ernest ORCID: https://orcid.org/0000-0003-4459-8609, Bagot, Martine and Bonnet, Marion ORCID: https://orcid.org/0000-0002-7559-2413 2023. Epidermal IL-33 drives inflammation in necroptosis-induced skin inflammation by recruiting TNF-producing immune cells. [Online]. bioRXiv: bioRXiv.

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Abstract

Caspase-8 deficiency in the epidermis (caspase-8 EKO) 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-8 EKO animals. IL-33 is highly expressed in necroptotic epidermis of caspase-8 EKO 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.

Item Type:	Website Content
Date Type:	Published Online
Status:	Submitted
Schools:	Schools > Medicine
Subjects:	R Medicine > RL Dermatology
Publisher:	bioRXiv
Funders:	MRC, Cardiff University CMU Fellowship, European Skin Research Foundation
Last Modified:	10 Feb 2024 02:22
URI:	https://orca.cardiff.ac.uk/id/eprint/161656

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