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In murine peritoneal and other serous cavities, Gata6 drives identity of the major resident cavity macrophage population, with a smaller subset of cavity macrophages dependent upon Irf4. Here we show that Gata6+ macrophages in the human peritoneum are rare, regardless of age. Instead, many aligned with CD206+LYVE1+ mouse cavity macrophages from a differentiation stage just preceding expression of Gata6. The comparatively low abundance of CD206+ converting macrophages in healthy C57BL/6J mice was sustained after high-fat diet feeding or in mice capture from the wild, suggesting that the major resident macrophages between the species share overlapping differentiation programs but differing predispositions to distinct differentiation stages. Irf4-dependent mouse serous cavity macrophages aligned closely with CD1c+CD14+CD64+ human peritoneal dendritic cells (DCs) that, in turn, resembled CD1c+CD14-CD64- peritoneal cDC2. Peritoneal DC1 and plasmacytoid DCs were rare in both species. This cross-species resource comparing mouse and human serous cavity immune cells will facilitate translational research.

Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here, we reveal glutaminase (Gls) 1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis. In addition, impaired macrophage glutaminolysis exacerbated atherosclerosis, a condition during which efficient apoptotic cell debris clearance is critical to limit disease progression. Gls1 expression strongly correlated with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling revealed that macrophage efferocytic capacity rely on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase (Glud1) to fuel ɑ-ketogulatrate-dependent immunometabolism. This pathway was 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.