Contributions of Myeloid Peroxisomes to Inflammation in Heart

About This Grant

Project Summary/Abstract Myocardial infarction (MI) is one of the most prevalent diseases in the United States and worldwide. A characteristic of the post-MI tissue response includes a rapid inflammatory response. The intensity and duration of this inflammatory response are critical in determining extent of death of cardiomyocytes, progression of the immune response towards anti-inflammatory and pro-repair type, and the extent of fibrosis. Hence, inflammation and its timely resolution can affect organism survival, tissue damage and heart function post-injury. Clinically, excessive inflammation has also been shown to be directly correlated to long-term heart failure and mortality after MI. Inflammation-targeting therapies have been tried in the clinical trials, yet we can do better. Following cardiac injury, the inflammatory response includes infiltration of neutrophils and macrophages (Mφ) into the injured tissue. The resolution of this inflammatory response is an active process in which Mφs play a vital role by engulfing dying cells and apoptotic inflammatory immune cells by a process called efferocytosis. This leads to the production of anti-inflammatory cytokines like IL-10, TGF-β, and bioactive lipids like lipoxins. Mφ metabolism is also intertwined with its functional response as inflammatory Mφs prioritize glycolysis while anti-inflammatory Mφs appear to utilize oxidative phosphorylation to a higher degree. The efferocytic Mφ can utilize fatty acids derived from engulfed cells for oxidative metabolism in mitochondria and facilitate repair functions post injury. Peroxisomes are cellular organelles that have important functions in cellular fatty acid sensing and metabolism. These organelles have the unique ability to metabolize very-long-chain fatty acids (VLCFA) in cells. Our preliminary data suggest a spatial localization of peroxisomes surrounding apoptotic cells, as well as induction of peroxisomal β-oxidation and accumulation of VLCFAs in Mφs during efferocytosis. My experiments further imply that VLCFA metabolism regulates cytokine production and polarization of Mφs following efferocytosis. I hypothesize that Mφ peroxisomal VLCFA metabolism regulates the tissue repair response after injury through altering immunometabolic signaling that controls cytokine production, and in turn, the efficiency of organ repair. My hypothesis will be tested through molecular mechanistic studies that identify causal determinants of peroxisomal signaling in Mφs, and consequences on tissue damage, organ function, and inflammation. My studies also have the potential to uncover new targets for the enhancement of the tissue repair.