Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Centre National de la Recherche Scientifique (CNRS) (R.G.), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, Nice, France.
Computer Technologies Department, ITMO University, Saint Petersburg, Russia.
Nat Metab. 2021 Oct;3(10):1313-1326. doi: 10.1038/s42255-021-00471-y. Epub 2021 Oct 14.
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.
巨噬细胞依赖于紧密整合的代谢重排，通过吞噬作用清除稳态和疾病期间濒死的邻近细胞。在这里，我们揭示了谷氨酰胺酶-1 介导的谷氨酰胺分解代谢对于巨噬细胞在稳态期间清除凋亡细胞至关重要。此外，巨噬细胞谷氨酰胺分解代谢受损会加剧动脉粥样硬化，在这种情况下，有效地清除凋亡细胞碎片对于限制疾病进展至关重要。谷氨酰胺酶-1 的表达与心血管疾病患者的动脉粥样硬化斑块坏死强烈相关。高通量转录组和代谢组学分析显示，巨噬细胞吞噬作用的能力依赖于非经典转氨基途径，而不依赖于谷氨酸脱氢酶为依赖α-酮戊二酸的免疫代谢提供燃料的传统要求。该途径是满足吞噬作用对细胞解毒和高能细胞骨架重排的独特要求所必需的。因此，我们在小鼠和人类中发现了非经典谷氨酰胺代谢在清除死亡细胞和维持组织稳态方面的作用，无论是在健康还是疾病状态下。
