Abstract
Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here we reveal that glutaminase-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. Glutaminase-1 expression strongly correlates with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling reveals that macrophage efferocytic capacity relies on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase to fuel ɑ-ketoglutarate-dependent immunometabolism. This pathway is necessary to meet the unique requirements of efferocytosis for cellular detoxification and high-energy cytoskeletal rearrangements. Thus, we uncover a 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.
Original language | English (US) |
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Pages (from-to) | 1313-1326 |
Number of pages | 14 |
Journal | Nature Metabolism |
Volume | 3 |
Issue number | 10 |
DOIs | |
State | Published - Oct 2021 |
Funding
We thank B. Caraveo for computional development of DreamBio, a new topological tool for Integrated Network Analysis. N. Grandchamp provided Lenti-ONE AOX vector through GEG Tech. We thank S. Fernandez for the noninvasive study of atheroma plaques by ultrasound echography as part of the European Center for Research in Imaging (Cerimed), F. Labret for assistance with flow cytometry, V. Corcelle for assistance in animal facilities and M. Irondelle for assistance with confocal microscopy. This work was supported by grants from the Fondation de France, ANR and the European Research Council consolidator program (ERC2016COG724838) to L.Y.-C. CCMA electron microscopy equipment was funded by the R\u00E9gion Sud - Provence-Alpes-C\u00F4te d\u2019Azur, the Conseil D\u00E9partemental des Alpes Maritimes and the GIS-IBiSA.
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
- Physiology (medical)
- Cell Biology