The discovery “opens the door to the introduction of metabolic hormones (ghrelin and leptin) in immunology and microbiology,” according to Kubes Lab’s principal investigator and his research group.
“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,” said Kubes.
The researchers’ next step is to better understand how immune cells like neutrophils function during infection. They are particularly curious about how infections are cleaned from neutrophils and whether neutrophils do other tasks besides clearing bacteria.
The interdisciplinary work of this research team is the result of 133 independent experiments conducted in collaboration with the labs of Dr. Keith Sharkey, Ph.D. (Snyder Institute, Hotchkiss Brain Institute (HBI)), Dr. Jeff Biernaskie, Ph.D. (HBI and Alberta Children’s Hospital Research Institute), and researchers from University Hospital Regensburg, Germany, and Texas A&M University.
Canadian Institutes of Health Research has funded the study.
During infection, inflammatory monocytes are thought to be key for bacterial eradication, but this is hard to reconcile with the large numbers of neutrophils that are recruited for each monocyte that migrates to the afflicted tissue and the much more robust microbicidal functions of the neutrophils. However, unlike neutrophils, monocytes have the capacity to convert to situationally specific macrophages that may have critical functions beyond infection control1,2. Here, using a foreign body coated with Staphylococcus aureus and imaging over time from cutaneous infection to wound resolution, we show that monocytes and neutrophils are recruited in similar numbers with low-dose infection but not with high-dose infection and form a localization pattern in which monocytes surround the infection site, whereas neutrophils infiltrate it. Monocytes did not contribute to bacterial clearance but converted to macrophages that persisted for weeks after infection, regulating hypodermal adipocyte expansion and production of the adipokine hormone leptin. In infected monocyte-deficient mice, there was increased persistent hypodermis thickening and an elevated leptin level, which drove overgrowth of dysfunctional blood vasculature and delayed healing with a thickened scar. Ghrelin, which opposes leptin function3, was produced locally by monocytes, and reduced vascular overgrowth and improved healing post-infection. In sum, we find that monocytes function as a cellular rheostat by regulating leptin levels and revascularization during wound repair.