Kavli Affiliate: Daniel S. Mucida, Elaine Fuchs
| Authors: Siqi Liu, Yun Ha Hur, Xin Cai, Qian Cong, Yihao Yang, Chiwei Xu, Angelina M Bilate, Kevin Andrew Uy Gonzales, Christopher J. Cowley, Brian Hurwitz, Ji-Dung Luo, Tiffany Tseng, Shiri Gur-Cohen, Megan Sribour, Tatiana Omelchenko, John Levorse, H Amalia Pasolli, Criag B Thompson, Daniel Mucida and Elaine Fuchs
| Summary:
ABSTRACT Pathogen infection and tissue injury are universal insults that disrupt homeostasis. Innate immunity senses microbial infections and induces interferons (IFNs) to activate resistance mechanisms. Applying unbiased phylogenetic analysis, we show that interleukin-24 (IL24) is among the closest evolutionary homologs to the IFN family and shares a common ancestral origin. However, in contrast to IFNs, IL24 induction occurs specifically in barrier epithelial progenitors after injury and is independent of microbiome or adaptive immunity. Surprisingly, Il24 ablation impedes not only epidermal proliferation and re-epithelialization, but also capillary and fibroblast regeneration within the dermal wound bed. Conversely, ectopic Il24 induction in homeostatic epidermis triggers global epithelial-mesenchymal tissue repair responses. Mechanistically, sustained Il24 expression depends upon both IL24 receptor/STAT3 signaling and also hypoxia-stabilized HIF1α, which converge following injury. Thus, parallel to the IFN-mediated innate immune sensing of pathogens to resolve infections, epithelial stem cells sense injury signals to orchestrate IL24-mediated tissue repair. Competing Interest Statement E.F. is a former member of the scientific advisory boards of LOreal and Arsenal Biosciences and owns stock futures with Arsenal Biosciences. C.B.T. is a founder of Agios Pharmaceuticals and a member of its scientific advisory board. He is on the Board of Directors for Regeneron and also a former member of the Board of Directors and stockholder of Merck and Charles River Laboratories. The other authors declare that they have no competing interests.