Abstract
Pathogen infection and tissue injury are universal insults that disrupt homeostasis. Innate immunity senses microbial infections and induces cytokines/chemokines to activate resistance mechanisms. Here, we show that, in contrast to most pathogen-induced cytokines, interleukin-24 (IL-24) is predominately induced by barrier epithelial progenitors after tissue injury and is independent of microbiome or adaptive immunity. Moreover, Il24 ablation in mice impedes not only epidermal proliferation and re-epithelialization but also capillary and fibroblast regeneration within the dermal wound bed. Conversely, ectopic IL-24 induction in the homeostatic epidermis triggers global epithelial-mesenchymal tissue repair responses. Mechanistically, Il24 expression depends upon both epithelial IL24-receptor/STAT3 signaling and hypoxia-stabilized HIF1α, which converge following injury to trigger autocrine and paracrine signaling involving IL-24-mediated receptor signaling and metabolic regulation. Thus, parallel to innate immune sensing of pathogens to resolve infections, epithelial stem cells sense injury signals to orchestrate IL-24-mediated tissue repair.
Original language | English (US) |
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Pages (from-to) | 2127-2143.e22 |
Journal | Cell |
Volume | 186 |
Issue number | 10 |
DOIs | |
State | Published - May 11 2023 |
Keywords
- STAT3
- angiogenesis
- coordinated tissue repair
- epithelial stem cells
- hypoxia
- innate immune signaling
- interferons
- interleukin-24
- microbiome-independent responses
- tissue injury
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology