Digestive Hormones Found to Significantly Influence Infectious Wound Healing

By Brittany Wade 

September 13, 2022 | Neutrophils and monocytes—two types of white blood cells—are widely recognized for their primary roles in the fight against bacteria-infected wounds. The longstanding assumption was that each cell type contributed equally to eradicating infectious microbes. However, the University of Calgary research team not only discovered that neutrophils and monocytes play distinct roles in wound healing but that digestive hormones contribute to immune function. 

The two hormones, leptin and ghrelin, have emerged as significant influencers in wound repair. Leptin, often called the satiety hormone, is primarily produced by adipocytes (fat storage cells) after the body accumulates enough energy to maintain function. In contrast, specialized cells in the stomach and pancreas produce ghrelin to incite hunger when energy supplies are low.  

Remarkably, these hormones—previously relegated to the digestive system—now demonstrate dual functions as potential immunomodulators.  

“While translating our research from bench to bedside will require many more experiments and involve a model more closely related to human disease, it is exciting that we have made a fundamental discovery that could improve infections and tissue repair in humans, especially hard-to-treat cases,” said first author Rachel Kratofil, Ph.D., in a press release. 

Immune Dynamics 

In response to wound infections, the immune system deploys white blood cells and launches a healing cascade. Neutrophils are the first responders, infiltrating to phagocytize foreign invaders. Monocytes were thought to behave similarly, while macrophages—another type of immune cell and close relative of monocytes—facilitated wound repair. 

As outlined in a Nature paper (DOI: 10.1038/s41586-022-05044-x), the research team learned that while neutrophils perform the bulk of bacterial eradication, monocytes influence leptin and ghrelin concentrations to foster tissue repair. Additionally, monocytes eventually differentiated into macrophages, contradicting the longstanding belief that only tissue-resident macrophages, not circulating monocytes, repair the skin post-wound.  

After exposing wild-type and monocyte-deficient mice to Staphylococcus aureus—a common pathogen associated with skin damage—the team monitored live immune cell dynamics using multiphoton intravital microscopy. This type of microscopy is a specialized in vivo imaging technique unique to the Kubes Lab, named after Paul Kubes, Ph.D., principal investigator and co-senior author. 

Approximately 24 hours post-injury, neutrophils were the only immune cells to make physical contact with S. aureus. They also significantly decreased bacterial burden to the same degree in both mouse types, regardless of monocyte presence. 

“This research is important because it indicates a paradigm shift challenging the current thinking that neutrophils and monocytes clear bacteria. Our study elevates the role of monocytes in wound repair,” explains Kratofil. 

Hormone-Mediated Wound Healing 

In monocyte-deficient mice, the team noticed an exaggeration in dilated vasculature, inappropriate angiogenesis (new blood vessel growth), and slower wound healing times. These mice also contained enlarged adipocytes with increased leptin expression. However, when treated with a superactive mouse leptin antagonist (SMLA), their symptoms resolved, mimicking the healthy healing process of wild-type mice. 

Since ghrelin and leptin have opposing effects on the digestive system, the team wondered if ghrelin could also counteract leptin’s angiogenic traits, similar to SMLA. Interestingly, exogenous ghrelin showed improved wound healing 14 days post-infection, around the same time monocytes typically infiltrate the injury site and differentiate into macrophages. 

The team postulated that monocytes must play a role in counteracting excessive leptin expression through the local production of ghrelin. Their suspicions were confirmed when they discovered ghrelin mRNA in the infected skin of wild-type mice after the anticipated 14 days. Moreover, a separate test with mice containing ghrelin-deficient bone marrow produced similar results to mice without monocytes, demonstrating that hematopoietic-derived ghrelin is essential for wound healing. 

Thus, the study suggests that ghrelin curbs immune leptin expression and facilitates healthy wound repair. While neutrophils are the primary fighters against bacteria via phagocytosis, monocytes mainly regulate hormone production. 

“It will be interesting, for example, to see how ghrelin and leptin respond in other disease models such as sterile injury or cancer, and to learn how these processes are altered when a patient has multiple simultaneous diseases or conditions such as obesity and diabetes,” says Kubes. 

This digestive hormone-immune phenomenon likely explains, in part, why patients with increased leptin levels, such as those with diabetes, may be more susceptible to infected wounds with extended healing times. Furthermore, since angiogenesis is a critical component of cancer formation and tumor growth, leptin-mediated angiogenesis and its antagonist ghrelin could comprise a compelling new area of oncological study.