Metabolic regulation of inflammation during tissue repair - Tissue injury requires the proper establishment of a dynamic inflammatory niche to clear invading pathogens and damaged cells, and then to promote tissue repair. Clinical cases of poor wound healing are marked by prolonged inflammation, often associated with immune dysfunction, which leads to tissue damage and a spectrum of pathological outcomes. Inflammation immediately after injury is largely driven by early-stage monocyte-derived macrophages and neutrophils, and so understanding the mechanisms that control inflammation in these cell types will provide new therapeutic treatment options. There is increasing interest in how changes in metabolism control the phenotypes of macrophages and other immune cells by regulating signaling and gene expression that are central to activation, including inflammation. Recently, our laboratories uncovered an unexpected and intriguing role for glutamine metabolism in regulating macrophage function in skin wound healing. In particular, we found that mice fed glutamine-deficient diets have prolonged inflammation and defective wound repair. Our data further reveal that glutamine regulates specific subsets of inflammatory genes and epigenetic changes in macrophages. Therefore, the overall objective of this proposal is to define the contributions of metabolic regulation of macrophages to skin wound healing. Our central hypothesis is that glutamine metabolism controls the inflammatory niche during tissue repair in the skin and macrophages are the primary mediators of this response. This hypothesis is based on our findings that: 1) macrophages display altered metabolic profiles during early and mid-stage repair; 2) the inflammatory niche is altered in mouse wounds that lack glutamine metabolism in monocyte-derived cells; 3) glutamine metabolism alters the inflammatory gene expression of macrophages. Through three focused and complementary Specific Aims, we will (1) identify the role of glutamine metabolism after injury in vivo and in human macrophages in vitro, (2) define how glutamine metabolism impacts epigenetic regulation and redox signaling in skin wounds, and (3) examine the impact of diabetes on glutamine metabolism during skin repair. The work proposed in this application is innovative because it will take advantage of multiple genetic mouse models that allow specific depletion of glutamine metabolism, and state-of-the-art genomics and systems analysis of mouse and human wound data. The proposed research is significant because it will provide information about the precise function of glutamine in skin repair in vivo, which is currently poorly understood. The rationale for this research is that amino acid enriched dietary supplementation can improve chronic diabetic wounds, which impacts over 4 million patients in the US and over 7 million worldwide, but more information about the mechanisms is needed to optimize therapeutic applications. Our proposed studies will identify specific mechanisms that can be utilized to promote healing in human patients with defective wound healing or inflammatory disorders.
