How injury is sensed by the host to coordinate organ-level repair remains unclear. In Cell, Liu et al. show that wound-induced hypoxia triggers autocrine signaling through the interferon homologue IL-24 and the transcription factor STAT3 to coordinate re-epithelialization and healing, independently of pathogen-sensing or adaptive immunity. IL-24 is specifically induced 24 hours after injury in epidermal stem cells (EpSCs) near the wound site and at day 3 in EpSCs in the re-epithelializing tongue. This induction is observed in germ-free, Myd88−/−Trif−/− or Rag2−/−Il2rg−/−mice, which indicates that it is independent of microorganisms, pathogen-induced signals, or adaptive immune cells. Il24−/− or Il20rb−/− mice, which lack the receptor subunit specifically used by IL-24, have reduced EpSC activation of STAT3, which is essential for epithelial regeneration, thinner re-epithelialization tongues that lack proliferating blood vessels and type I collagen deposition, and defective migration patterns of ARG1+ and MHCII+ macrophages, which are required for angiogenesis and cleaning of the cellular debris. The hypoxia-induced transcription factor HIF1α is induced in the wounded epithelium, and its deletion in the epidermis, as well as deletion of STAT3, results in loss of Il24 mRNA, which indicates that hypoxia and STAT3 activation regulate an autocrine IL-24 signaling pathway in EpSCs for skin repair.
This is a preview of subscription content, access via your institution