Institute of Cellular and System Medicine, National Health Research Institute, Miaoli, Taiwan.
Department of Fundamental Oncology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
Nat Immunol. 2023 Mar;24(3):452-462. doi: 10.1038/s41590-023-01430-3. Epub 2023 Feb 23.
Exposure of lipopolysaccharide triggers macrophage pro-inflammatory polarization accompanied by metabolic reprogramming, characterized by elevated aerobic glycolysis and a broken tricarboxylic acid cycle. However, in contrast to lipopolysaccharide, CD40 signal is able to drive pro-inflammatory and anti-tumorigenic polarization by some yet undefined metabolic programming. Here we show that CD40 activation triggers fatty acid oxidation (FAO) and glutamine metabolism to promote ATP citrate lyase-dependent epigenetic reprogramming of pro-inflammatory genes and anti-tumorigenic phenotypes in macrophages. Mechanistically, glutamine usage reinforces FAO-induced pro-inflammatory and anti-tumorigenic activation by fine-tuning the NAD/NADH ratio via glutamine-to-lactate conversion. Genetic ablation of important metabolic enzymes involved in CD40-mediated metabolic reprogramming abolishes agonistic anti-CD40-induced antitumor responses and reeducation of tumor-associated macrophages. Together these data show that metabolic reprogramming, which includes FAO and glutamine metabolism, controls the activation of pro-inflammatory and anti-tumorigenic polarization, and highlight a therapeutic potential of metabolic preconditioning of tumor-associated macrophages before agonistic anti-CD40 treatments.
脂多糖（LPS）的暴露会引发巨噬细胞的促炎极化，伴随着代谢重编程，表现为有氧糖酵解和三羧酸循环的破坏。然而，与 LPS 相反，CD40 信号能够通过一些尚未定义的代谢编程来驱动促炎和抗肿瘤极化。在这里，我们表明 CD40 的激活触发脂肪酸氧化（FAO）和谷氨酰胺代谢，以促进 ATP 柠檬酸裂解酶依赖性促炎基因和巨噬细胞抗肿瘤表型的表观遗传重编程。在机制上，通过谷氨酰胺到乳酸的转化来精细调节 NAD/NADH 比，谷氨酰胺的利用增强了 FAO 诱导的促炎和抗肿瘤激活。涉及 CD40 介导的代谢重编程的重要代谢酶的遗传缺失消除了激动性抗 CD40 诱导的抗肿瘤反应和肿瘤相关巨噬细胞的再教育。总之，这些数据表明，包括 FAO 和谷氨酰胺代谢在内的代谢重编程控制着促炎和抗肿瘤极化的激活，并强调了在激动性抗 CD40 治疗之前对肿瘤相关巨噬细胞进行代谢预处理的治疗潜力。
