A tissue injury sensing and repair pathway distinct from host pathogen defense

Cell. 2023 May 11;186(10):2127-2143.e22. doi: 10.1016/j.cell.2023.03.031. Epub 2023 Apr 24.


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.

Keywords: STAT3; angiogenesis; coordinated tissue repair; epithelial stem cells; hypoxia; innate immune signaling; interferons; interleukin-24; microbiome-independent responses; tissue injury.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptive Immunity
  • Animals
  • Chemokines
  • Cytokines*
  • Epidermis
  • Immunity, Innate
  • Mice
  • Wounds and Injuries* / immunology


  • Chemokines
  • Cytokines
  • Il24 protein, mouse