Here, Liu et al. detail how epithelial stem cells (ESCs) are able to sense injury and initiate tissue repair independently of microbial signals. They show that during skin wounding in mice, ESCs at the wound edge upregulate IL-24, which drives STAT3 activation in an autocrine and paracrine manner to promote wound repair. Notably, this IL-24-mediated process still occurs in germ-free mice and in the absence of adaptive immune cells. Mice in which IL-24 signalling was ablated showed defects in re-epithelialization, in regeneration of blood vessels and in fibroblast responses in the wound bed. The authors found that induction of IL-24 at the wound edge requires both hypoxia-mediated stabilization of HIF1α and autocrine IL-24 receptor signalling. They suggest this leads to natural autoregulation of the repair response, as re-establishment of the vasculature during wound healing will reduce hypoxia- and IL-24-mediated signalling. Interestingly, they highlight that prominent IL-24 expression has been reported in certain diseases that have been associated with dysfunctional tissue repair, including severe COVID-19 and ulcerative colitis.