Department of Molecular Metabolism, Division of Biological Sciences, Harvard TH Chan School of Public Health, Boston, United States.
School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Elife. 2020 May 12;9:e54090. doi: 10.7554/eLife.54090.
Metabolic pathways and inflammatory processes are under circadian regulation. Rhythmic immune cell recruitment is known to impact infection outcomes, but whether the circadian clock modulates immunometabolism remains unclear. We find that the molecular clock Bmal1 is induced by inflammatory stimulants, including Ifn-γ/lipopolysaccharide (M1) and tumor-conditioned medium, to maintain mitochondrial metabolism under metabolically stressed conditions in mouse macrophages. Upon M1 stimulation, myeloid-specific knockout (M-BKO) renders macrophages unable to sustain mitochondrial function, enhancing succinate dehydrogenase (SDH)-mediated mitochondrial production of reactive oxygen species as well as Hif-1α-dependent metabolic reprogramming and inflammatory damage. In tumor-associated macrophages, aberrant Hif-1α activation and metabolic dysregulation by M-BKO contribute to an immunosuppressive tumor microenvironment. Consequently, M-BKO increases melanoma tumor burden, whereas administering the SDH inhibitor dimethyl malonate suppresses tumor growth. Therefore, Bmal1 functions as a metabolic checkpoint that integrates macrophage mitochondrial metabolism, redox homeostasis and effector functions. This Bmal1-Hif-1α regulatory loop may provide therapeutic opportunities for inflammatory diseases and immunotherapy.
代谢途径和炎症过程受昼夜节律调节。已知节律性免疫细胞募集会影响感染结果，但昼夜节律钟是否调节免疫代谢仍不清楚。我们发现，分子钟 Bmal1 被炎症刺激物诱导，包括 Ifn-γ/脂多糖（M1）和肿瘤条件培养基，以在代谢应激条件下维持小鼠巨噬细胞中的线粒体代谢。在 M1 刺激下，髓系特异性 敲除（M-BKO）使巨噬细胞无法维持线粒体功能，增强琥珀酸脱氢酶（SDH）介导的线粒体产生活性氧以及 Hif-1α依赖性代谢重编程和炎症损伤。在肿瘤相关巨噬细胞中，M-BKO 导致异常的 Hif-1α激活和代谢失调，导致免疫抑制的肿瘤微环境。因此，M-BKO 增加了黑色素瘤肿瘤负担，而施用 SDH 抑制剂二甲基丙二酸可抑制肿瘤生长。因此，Bmal1 作为代谢检查点，整合了巨噬细胞线粒体代谢、氧化还原平衡和效应功能。这个 Bmal1-Hif-1α 调节回路可能为炎症性疾病和免疫治疗提供治疗机会。
