Bmal1 integrates mitochondrial metabolism and macrophage activation
Bmal1 integrates mitochondrial metabolism and macrophage activation
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DOI：
10.7554/elife.54090
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发表时间：
2020-05-12
期刊：
影响因子：
7.7
通讯作者：
Lee, Chih-Hao
中科院分区：
文献类型：
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作者：
Alexander, Ryan K.;Liou, Yae-Huei;Lee, Chih-Hao
代谢途径和炎症过程受昼夜节律调节。已知有节律的免疫细胞募集会影响感染结果，但生物钟是否调节免疫代谢仍不清楚。我们发现，分子时钟Bmal 1诱导的炎症刺激，包括IFN-γ/脂多糖（M1）和肿瘤条件培养基，以维持小鼠巨噬细胞代谢应激条件下的线粒体代谢。在M1刺激后，骨髓特异性Bmal 1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）介导的活性氧的线粒体产生以及Hif-1 α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引起的异常Hif-1 α活化和代谢失调导致免疫抑制性肿瘤微环境。因此，M-BKO增加黑色素瘤肿瘤负荷，而给予SDH抑制剂丙二酸二甲酯抑制肿瘤生长。因此，Bmal 1作为一个代谢检查点，整合巨噬细胞线粒体代谢，氧化还原稳态和效应器功能。这种Bmal 1-HIF-1 α调节环可能为炎症性疾病和免疫疗法提供治疗机会。
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-gamma/lipopolysaccharide (M1) and tumor-conditioned medium, to maintain mitochondrial metabolism under metabolically stressed conditions in mouse macrophages. Upon M1 stimulation, myeloid-specific Bmal1 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-1 alpha-dependent metabolic reprogramming and inflammatory damage. In tumor-associated macrophages, aberrant Hif-1 alpha 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-1 alpha regulatory loop may provide therapeutic opportunities for inflammatory diseases and immunotherapy.