Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation

Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here, we reveal that glutaminase (GLS) 1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis in mice. In addition, impaired macrophage glutaminolysis exacerbates atherosclerosis, a condition during which efficient apoptotic cell debris clearance is critical to limit disease progression. Gls1 expression strongly correlates with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling revealed that macrophage efferocytic capacity relies on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase (GLUD1) to fuel ɑ-ketogulatrate-dependent immunometabolism. This pathway is necessary to meet the unique requirements of efferocytosis for cellular detoxification and high energy cytoskeletal rearrangements. Thus, we uncovered a novel role for non-canonical glutamine metabolism for efficient clearance of dying cells and maintenance of tissue homeostasis during health and disease in mouse and humans Peritoneal cavity macrophages (PCMs) were obtained from Gls1 fl/fl mice and LysM-Cre x Gls1 fl/fl mice. Mice were i.p injected with saline or with IL-4 complexed to anti-IL-4 mAb. Then, 36 hours later, PCMs were collected by lavage with 5ml of PBS and stained with CD64 (Brilliant Violet 421 conjugated), ICAM-2 (Alexa Fluor 647 conjugated) and CD115 (PE conjugated) before cell sorting.