Can’t Do It Alone: How the Skin Relies on the Immune System for Wound Healing

The Context: It was long thought that our body’s capacity to repair wounds relied entirely on skin cells, which are able to sense low levels of oxygen at the injury site, leading to their migration across the lesion. However, this did not explain why wounds were not properly healed in individuals with compromised immune systems, suggesting that the immune response may play a role as well.

The Study: Healing damaged epithelium requires special signals from the immune system, finds a new study published in Science by NYSCF – Robertson Stem Cell Investigator Shruti Naik, PhD of the New York University Grossman School of Medicine. Dr. Naik’s work shows that the gamma delta subset of T cells gather in high numbers at the edge of wounds and secrete IL-17a, a molecule that is essential in triggering skin cells to migrate and cover the wound.

The Importance: These findings paint a more complete picture of skin regeneration in wound repair, and because IL-17a is implicated in numerous autoimmune and inflammatory conditions, these results could provide important insights into understanding and treating these diseases.

When we get a cut or burn, our body swiftly jumps into action to heal the wound and restore the physical barrier that protects us from external threats. But how does the skin repair itself? Scientists had long believed that our body’s wound repair system relied entirely on the ability of epithelial cells on the outermost layer of our skin to sense the low levels of oxygen in the site of injury, prompting them to migrate over the wound. 

However, some researchers, including Dr. Naik, suspected that this was not the whole story. They had previously noticed that in people and animals with weakened immune systems, epithelial cells don’t perform their wound healing duties as well. This observation encouraged Dr. Naik to explore a potential role for the immune system in wound repair.

T Cells to the Rescue

Dr. Naik’s team started investigating the different types of immune cells present in skin injuries. They found that among the T cells in our blood that fight off intruders, a subset called gamma delta would flock to the periphery of the wounds.

The authors realized that these gamma delta T cells were making a lot of a specific cytokine, or immune-signaling molecule called IL-17a. IL-17a appeared to be signaling to epithelial cells “hey, there’s a wound over here!” which prompted the epithelial cells to start migrating across the wound and heal it. This observation pinpointed a surprising new link between the immune system and epithelial repair. 

Digging Deeper into the Immune-Epithelial Connection

A question then remained: how exactly does IL-17a signal to epithelial cells to start healing a wound?

To answer this, the authors analyzed two conditions in which IL-17a cannot act: in mice without gamma delta T cells, and in mice lacking the receptor for IL-17a on the surface of epithelial cells. In both cases, the team noticed that a protein called HIF1a —which plays an integral role in the body’s response to low oxygen levels and wound repair— was missing in epithelial cells. Thus, in the absence of IL-17a, epithelial cells could not activate HIF1a, which in turn prevented mice from properly healing skin injuries.

With this, the authors discovered not only how IL-17a promotes wound repair, but also revealed a requirement for the immune system in epithelial healing.

These findings overthrow a long-held view about how epithelial cells themselves kickstart the healing response after injury. The authors believe these results could have implications for several autoimmune conditions, including inflammatory bowel disease and psoriasis, where IL-17a plays a central role. They could also be informative in understanding and fighting cancer, given that HIF1a is a known driver of tumor progression. 

Journal Article:

Interleukin-17 governs hypoxic adaptation of injured epithelium
Piotr Konieczny, Yue Xing, Ikjot Sidhu, Ipsita Subudhi, Kody P Mansfield, Brandon Hsieh, Douglas E Biancur, Samantha B Larsen, Michael Cammer, Dongqing Li, Ning Xu Landén, Cynthia Loomis, Adriana Heguy, Anastasia N Tikhonova, Aristotelis Tsirigos & Shruti Naik. Science. 2022. DOI: https://doi.org/10.1126/science.abg9302