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

Siqi Liu, Yun Ha Hur, Xin Cai, Qian Cong, Yihao Yang, Chiwei Xu, Angelina M. Bilate, Kevin Andrew Uy Gonzales, S. Martina Parigi, Christopher J. Cowley, Brian Hurwitz, Ji Dung Luo, Tiffany Tseng, Shiri Gur-Cohen, Megan Sribour, Tatiana Omelchenko, John Levorse, Hilda Amalia Pasolli, Craig B. Thompson, Daniel MucidaElaine Fuchs

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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 languageEnglish (US)
Pages (from-to)2127-2143.e22
JournalCell
Volume186
Issue number10
DOIs
StatePublished - 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

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