Necroptosis is a form of programmed necrosis dependent on Receptor Interacting Protein Kinase 3 (RIPK3) and Mixed Lineage Kinase domain Like pseudokinase (MLKL). It is antagonised by apoptotic effectors FADD and caspase-8. Necroptosis has been shown previously to trigger psoriasis-like skin inflammation in mice upon epidermal-specific deletion of FADD or caspase-8 (FADD or caspase-8EKO). Here, we show that alarmin IL-33 is highly expressed in necroptotic epidermis of caspase-8EKO mice and induces the inflammatory cascade upon keratinocyte necroptosis. Genetic ablation of IL-33 or its receptor ST2 (or IL-33R) dramatically delays lesion development and improves survival in caspase-8EKO animals. Interestingly, impairment of the IL33-IL33R axis does not affect epidermal necroptosis but reduces immune cell recruitment and subsequent amplification of inflammation. Recent data in the literature have highlighted expression IL-33 in the epidermis of psoriasis patients. Taken together, our findings highlight a pivotal role of IL-33 in necroptosis-induced psoriasis-like skin inflammation.

ESDR198 - Il-33 is a central mediator of necroptosis-induced skin inflammation.

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING