Our skin is the body’s largest organ and its most seamless defense against threats such as bacteria, viruses, accidents, and injuries. However, new research from Rockefeller University has revealed that the skin has an alternative protective mechanism that responds to injury signals in wounded tissue, such as low oxygen levels and scab formation, and doesn’t require an infection to activate. This is the first study to identify a damage response pathway distinct from the classical path triggered by pathogens.
A team of researchers has recently discovered an ancient mechanism for wound repair that has been conserved across different species.
The researchers focused on a group of organisms known as planarians, which can regenerate their entire bodies from small fragments. They found that planarians use a specific type of immune cell, called a macrophage, to repair wounds.
Interleukin-24 (IL24) is a protein induced in skin epithelial stem cells at the edge of a wound, and it plays a crucial role in wound healing. Once released, IL24 signals and coordinates various cells to repair the damaged tissue.
Fuchs, head of the Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, said, “IL24 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 IL24 receptor and respond to the signal. IL24 becomes an orchestrator that coordinates tissue repair.”
Biological systems maintain homeostasis by resolving disruptions such as pathogen infection and tissue injury. Barrier epithelial tissues like the skin are the first line of defense against external assaults. Upon condition, these tissues often sense pathogen-associated molecular patterns (PAMPs), activating a response that resists and eliminates pathogens. In the case of tissue injury, an immediate inflammatory response is triggered. However, the molecular details of how the host coordinates tissue-level repair remain unclear.
Recent studies have revealed a wound-induced signaling pathway that can be triggered independently of microbes or adaptive immunity. In this pathway, EpdSCs sense wound-induced hypoxia as a damage signal to activate interleukin-24 (IL-24), which coordinates tissue repair by promoting re-epithelialization, re-vascularization, dermal fibroblast proliferation, and collagen deposition. This IL-24-mediated response is similar to pathogen-induced IFN signaling in innate immunity but is molecularly distinct.
The body has defense mechanisms against pathogens, but how it responds to injury is poorly understood. New research has shown that a cytokine called IL24 plays a crucial role in wound healing, activating a pathway involving transcription factors HIF1a and STAT3. Epidermal stem cells sense the hypoxic environment of the wound, which induces a positive feedback loop that amplifies IL24 production at the wound edge.
This coordinated effort by various cell types expressing the IL24 receptor helps repair the wound. With IL24 functionality, the healing process is completed on time. IL24 may also be involved in the injury response in other organs. The researchers suspect that IL24 and interferons are evolutionarily related and may have diverged from a common molecular pathway dating back hundreds of millions of years.
The researchers also showed that the IL24 pathway is independent of germs, indicating that it functions specifically in response to tissue injury rather than as a defense against pathogens. In addition, they demonstrated that IL24 is necessary for efficient tissue repair, as mice lacking IL24 functionality exhibited delayed healing compared to normal mice.
Overall, the results of this experiment shed light on a previously unknown tissue repair pathway that is separate from the host-pathogen defense system and suggests that IL24 may play a key role in injury response in various organs throughout the body.
The host defense system protects against foreign pathogens. At the same time, an experiment studying a tissue injury sensing and repair pathway looks at how cells respond to injury without infectious agents. Results could reveal new mechanisms for tissue repair distinct from those for pathogen defense. These findings can lead to new therapeutic interventions for injuries and chronic diseases.
However, a general conclusion for an experiment studying a tissue injury sensing and repair pathway distinct from host-pathogen defense might be that it has identified new mechanisms and signaling pathways involved in tissue repair and regeneration. These mechanisms are different from those involved in pathogen defense. They can lead to new therapeutic interventions for injuries and chronic diseases. Further research could improve our understanding of how tissues heal after injury and lead to more effective treatments for various conditions.
- Siqi Liu, Yun Ha Hur, Craig B. Thompson, et al. A tissue injury sensing and repair pathway distinct from the host-pathogen defense.Cell DOI: 10.1016/j.cell.2023.03.031