Glutamine influx licenses macrophage glutaminolysis for restorative functions in atherosclerosis

Atherosclerotic plaque macrophages are key players at the site of disease, where metabolic reprogramming dictates whether they ameliorate or exacerbate pathogenesis. Here, we found that glutamine synthetase served as a metabolic rheostat controlling nutrient flux into cells in vitro, macrophage restorative functions in the context of atherosclerosis relied more heavily on glutamine influx and glutaminase activity. Cell-intrinsic regulation of glutaminolysis drives macrophage metabolic and transcriptional rewiring in atherosclerosis by diverting exogenous Gln flux to balance remodeling and restorative functions. Thus, we uncover a role of glutamine uptake upstream of glutaminolysis in atherosclerotic plaque development and stability. Bone marrow-derived macrophages were generated from Gls1-/- and control mice and cultured for the last 24h in presence or absence of interleukin-4 and glutamine synthase inhibitor (MSO). Atherosclerosis-prone Ldlr-/- mice were backrossed with or without Gls2-/- mice and served as recipients for transplantation of Gls1-/- or control bone marrow. Then, hyperlipidemia was induced in these mice by feeding them with an atherogenic diet (Western diet, TD88137, Ssniff) for 11 weeks. Peritoneal macrophages were obtained from all four genotypes at the end of the study.