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.

病原体感染和组织损伤是破坏体内平衡​​的普遍损伤。先天免疫感知微生物感染并诱导细胞因子/趋化因子激活抵抗机制。在这里，我们发现，与大多数病原体诱导的细胞因子相比，白介素 24 (IL-24) 主要由组织损伤后屏障上皮祖细胞诱导，并且独立于微生物组或适应性免疫。此外，小鼠体内的Il24消融不仅阻碍表皮增殖和再上皮化，而且阻碍真皮伤口床内的毛细血管和成纤维细胞再生。相反，稳态表皮中的异位 IL-24 诱导会触发整体上皮间质组织修复反应。从机械上讲，Il24表达依赖于上皮 IL24 受体/STAT3 信号传导和缺氧稳定的 HIF1α，它们在损伤后汇聚，触发涉及 IL-24 介导的受体信号传导和代谢调节的自分泌和旁分泌信号传导。因此，与通过先天免疫感知病原体来解决感染一样，上皮干细胞感知损伤信号以协调 IL-24 介导的组织修复。