Pro-resolving lipid mediators in immunity and vascular biology

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Project Summary/Abstract Impaired wound healing is a prominent clinical manifestation of chronic inflammatory diseases, such as obesity and type 2 diabetes (T2D). Acute wounds in individuals with T2D can become chronic and this is associated with sustained accumulation of pro-inflammatory leukocytes, prolonged edema, and fibrosis, leading to impaired wound closure (i.e. re-epithelialization). Functional lymphatic vessels are required for clearance of immune cells, edema, and host-defense, and several lines of evidence indicate that lymphatic clearance mechanisms are impaired in obesity and T2D. However, there are no current strategies to resolve inflammation, improve lymphatic function, and rescue defective tissue repair in obesity and T2D. In health, the acute inflammatory response that occurs during tissue injury is actively resolved, setting the stage for tissue repair. Pro-resolving lipid mediators, such as the resolvins, are critical mediators of active resolution of inflammation in part because they blunt inflammatory cytokine production and stimulate macrophage-mediated clearance of dead cells. We recently found that resolvins are generated in skin wounds and hasten tissue repair. Moreover, in work in progress, we discovered that specific receptors for resolvins are expressed on both macrophages and lymphatic vessels in skin wounds and that resolvin D2 (RvD2) reduces wound edema. Based on these exciting findings, we hypothesize that RvD2 engages its receptor on macrophages and lymphatic endothelial cells (LEC) to orchestrate clearance mechanisms during resolution to facilitate tissue repair. To this end, we propose to elucidate the role of RvD2 and its receptor in resolution of inflammation and edema during wound healing and determine the relative contribution of macrophages and LEC to this process by selectively deleting the RvD2 receptor in each cell type in vivo. We will uncover the mechanisms whereby RvD2 and its receptor regulate functions of macrophages and LEC important for resolution and edema clearance, and whether these processes can be rescued by RvD2 in obese-diabetic mice. Successful completion of these studies will uncover completely new roles of RvD2 and its receptor in macrophage and lymphatic function and could inform novel agonist-based approaches to rescue defective tissue repair in obesity and T2D, as well as other chronic inflammatory diseases.