Metabolic Control of Immune Cell Function in Atherogenesis

About This Grant

ABSTRACT Although lipid-lowering therapies have markedly decreased the incidence of atherosclerotic cardiovascular disease (ASCVD), it remains a major determinant of morbidity and mortality worldwide. Recent experimental and clinical evidence underscores the importance of inflammation in driving residual ASCVD risk; but the therapeutic potential of immunomodulation for ASCVD remains limited. In the last several years, intracellular metabolic reprogramming in immune cells has emerged as a key regulator of inflammation in ASCVD. Thus, further investigation into the immunometabolic regulatory networks that govern atheroprogression is predicted to reveal novel therapeutic approaches for ASCVD. Our lab has recently identified methylmalonic acid (MMA), a byproduct of propionyl-CoA catabolism, as vital to macrophage inflammatory processes that exacerbate atherogenesis. Loss-of-function mutations in key propionyl-CoA catabolism pathway enzymes, such as MMAB (cobalamin adenosyltransferase), lead to MMA accumulation. Circulating MMA levels predict cardiovascular mortality and increase with aging. Nevertheless, the causal role of MMA in ASCVD pathogenesis remains unknown. Recent reports demonstrate that MMAB is markedly downregulated in the aortas of patients with coronary artery disease compared to healthy controls, and in murine models of atherosclerosis, we have found that aortic and macrophage Mmab is significantly reduced. Moreover, our preliminary data show that genetic Mmab deficiency and exogenous MMA treatment exacerbate macrophage inflammasome activation, a key contributor to atheroprogression. The specific role that the MMAB-MMA metabolic axis plays in modulating macrophage inflammatory responses in the context of ASCVD remains to be determined. Our central hypothesis is that dysregulation of macrophage propionyl-CoA catabolism promotes atheroprogression through a novel immunometabolic MMA-mediated signaling axis. Using our newly generated myeloid-specific Mmab knockout mice, combined with state-of-the-art transcriptomics, metabolomics, flow cytometry, stable isotope tracer methodology, functional assays and STARNET datasets, we will (1) Elucidate the molecular mechanisms whereby MMA modulates inflammatory signaling in macrophages and (2) Determine the impact of the MMAB- MMA signaling axis on vascular inflammation and atherosclerosis. Completion of these aims will reveal how immunometabolic regulatory networks govern local and systemic inflammation during atheroprogression. Such networks can subsequently be leveraged to design targeted immune-based therapies for ASCVD.