Article ; Online: Staphylococcus aureus exacerbates dermal IL-33/ILC2 axis activation through evoking RIPK3/MLKL-mediated necroptosis of dry skin.
JCI insight
2024 Volume 9, Issue 6
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 ... ...
| 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. |
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| MeSH term(s) | Humans ; Mice ; Animals ; Immunity, Innate ; Staphylococcus aureus ; Interleukin-33/metabolism ; Necroptosis ; Lymphocytes ; Dermatitis, Atopic ; Inflammation/pathology ; Cytokines/metabolism ; Staphylococcal Infections ; Ichthyosis ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Protein Kinases/metabolism |
| Chemical Substances | Interleukin-33 ; Cytokines ; RIPK3 protein, human (EC 2.7.11.1) ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1) ; MLKL protein, human (EC 2.7.-) ; Protein Kinases (EC 2.7.-) ; MLKL protein, mouse (EC 2.7.-) |
| Language | English |
| Publishing date | 2024-02-06 |
| Publishing country | United States |
| Document type | Journal Article |
| ISSN | 2379-3708 |
| ISSN (online) | 2379-3708 |
| DOI | 10.1172/jci.insight.166821 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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