Examining the role of adenosine-sensing by macrophages in obesity-induced cardiac inflammation - PROJECT SUMMARY Tissue-resident macrophages fulfill various niche-specific functions to support tissue-level homeostasis. Obesity, however, impairs critical homeostatic functions of tissue-resident macrophages and triggers chronic low-grade inflammation by these cells to promote a spectrum of metabolic deficiencies. Neutralization of proinflammatory cytokines has yielded modest clinical efficacy in individuals with metabolic syndrome, type 2 diabetes, or cardiovascular disease. This has shifted the focus of potential immunotherapies to elucidating upstream signals driving disease phenotypes rather than targeting byproducts of inappropriate activation states. Extracellular metabolites can act as signaling molecules to control macrophage function in various disease contexts. Therefore, the purpose of this application is to uncover novel, tissue-specific metabolite-macrophage interactions that regulate metabolic inflammation in obesity. Metabolomic analysis of the interstitial fluid (IF) of different metabolic organs from mice fed a high-fat/high-sucrose diet uncovered adenosine as being the most upregulated metabolite in the heart IF of obese mice. Adenosine is a purine nucleoside intimately involved in feedback loops that maintain tissue integrity in response to cellular injury or stress. In line with this, the preliminary studies described in the proposal demonstrate that adenosine decreases metabolic-stress associated inflammation in macrophages. These findings led to the hypothesis that adenosine-sensing by cardiac macrophages represents an adaptive immunometabolic checkpoint that limits aberrant cardiac inflammation in obesity. This proposal describes two aims to test this hypothesis. Aim 1 will determine how the extracellular adenosine-macrophage axis regulates cardiac inflammation in obesity. Aim 2 will provide mechanistic insight into critical signaling pathways underscoring the immunosuppressive function of adenosine in metabolically activated macrophages. Overall, the experiments in the research proposal will provide a framework for therapeutic strategies focused on reducing cardiomyopathies in individuals with obesity. In addition to the research proposal, this application is equipped with a training plan to prepare the applicant for an academic career as a principal investigator studying how immune and cardiometabolic systems interact in health and disease. The applicant’s choice of sponsors, institutions, and career development activities place the applicant in an optimal environment to receive direct training in both immunology and cardiovascular physiology, as well as strengthen critical skills required to run an independent research program. Overall, the research and training goals described in this application will foster the development of an upcoming principal investigator set on contributing to the field of immunometabolism.
