Abstract
Atopic dermatitis (AD) is a persistent skin disease typified by symptoms of dry skin and recurrent eczema. Patients with AD are at heightened risk for Staphylococcus aureus infection. Group 2 innate lymphoid cells (ILC2s) are mainly activated by epithelial cell–derived cytokines IL-33 and involved in the pathogenesis of AD. However, little is known about the effect of skin delipidization on the epithelial cell–derived cytokines and dermal ILC2s in AD. In our study, we investigated the mechanism by which S. aureus infection modulates and exacerbates the pathogenesis of dry skin, leading to type 2 inflammation in the context of innate immunity. In vivo, we found that S. aureus infection aggravated delipidization-induced dermal IL-33 release and dermal ILC2 accumulation, which exacerbated skin inflammation. We also noticed that Il33fl/fl K14cre mice and Tlr2–/– mice exhibited attenuated skin inflammation. In vitro, treatment with necroptosis inhibitors reduced IL-33 release from S. aureus–infected keratinocytes. Mechanistically, we observed an increase in the necroptosis-associated kinases, MLKL and RIPK3, in S. aureus–infected mice, indicating that IL-33 release was associated with necroptotic cell death responses. Our results reveal that S. aureus infection–elicited keratinocyte necroptosis contributes to IL-33–mediated type 2 inflammation, which exacerbates the pathogenesis of dry skin.
Authors
Chia-Hui Luo, Alan Chuan-Ying Lai, Chun-Chou Tsai, Wei-Yu Chen, Yu-Shan Chang, Ethan Ja-Chen Chung, Ya-Jen Chang
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