Researchers from the lab of Rockefeller’s Elaine Fuchs, PhD, have uncovered an alternative protective mechanism that responds to injury signals in wounded tissue—including low oxygen levels from blood vessel disruption and scab formation.

The study is published in Cell in an article titled, “A tissue injury sensing and repair pathway distinct from host pathogen defense.”

“Pathogen infection and tissue injury are universal insults that disrupt homeostasis. Innate immunity senses microbial infections and induces cytokines/chemokines to activate resistance mechanisms,” wrote the researchers. “Here, we show that in contrast to most pathogen-induced cytokines, interleukin-24 (IL-24) is predominantly induced by barrier epithelial progenitors after tissue injury and is independent of microbiome or adaptive immunity.”

“IL-24 is predominately made by the wound-edge epidermal stem cells, but many cells of the skin—the epithelial cells, the fibroblasts, and the endothelial cells—express the IL-24 receptor and respond to the signal. IL-24 becomes an orchestrator that coordinates tissue repair,” explained Fuchs, who is head of the Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development.

In collaboration with Daniel Mucida’s lab at Rockefeller, the researchers worked with mice and found that the wound-induced IL24 signaling cascade is independent of germs.

“We learned that the epidermal stem cells sense the hypoxic environment of the wound,” says Yun Ha Hur, PhD, a research fellow in the lab and a co-first author on the paper.

Collaborating with Craig Thompson’s group at Memorial Sloan Kettering Cancer Center, the researchers showed that they could regulate IL-24 gene expression by changing oxygen levels.

Once the researchers discovered the origin of the tissue-repair pathway in epidermal stem cells, they studied the wound repair process in mice that had been genetically modified to lack IL-24 functionality.

“IL-24 could be working as a cue to signal the need for injury repair in many organs,” Hur said.

“Our findings provide insights into an important tissue damage sensing and repair signaling pathway that is independent of infections,” explained Fuchs.

An analysis with evolutionary biologist Qian Cong, PhD, at UT Southwestern Medical Center revealed that IL-24 and its receptors share close sequence and structure homology with the interferon family. The researchers suspect that these signaling molecules derive from a common molecular pathway dating far back in our past.

“We think that hundreds of millions of years ago, this ancestor might have diverged into two pathways—one being pathogen defense and the other being tissue injury,” Liu concluded.

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