Mitochondrial pyruvate carrier-mediated metabolism is dispensable for the classical activation of macrophages
Mitochondrial pyruvate carrier-mediated metabolism is dispensable for the classical activation of macrophages
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DOI：
10.1038/s42255-023-00800-3
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发表时间：
2023-05
影响因子：
20.8
通讯作者：
L. Ran;Song Zhang;Guosheng Wang;Pei Zhao;Jiaxing Sun;Jiaqi Zhou;Haiyun Gan;Ryounghoon Jeon;Qiang Li;J. Herrmann;Feilong Wang
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文献类型：
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作者：
L. Ran;Song Zhang;Guosheng Wang;Pei Zhao;Jiaxing Sun;Jiaqi Zhou;Haiyun Gan;Ryounghoon Jeon;Qiang Li;J. Herrmann;Feilong Wang
糖酵解对于巨噬细胞的经典激活（M1）是必不可少的，但糖酵解途径代谢物如何参与这一过程仍有待阐明。糖酵解产生丙酮酸，丙酮酸可以通过线粒体丙酮酸载体（MPC）运输到线粒体，然后在三羧酸循环中利用。基于使用MPC抑制剂UK5099的研究，线粒体途径被认为对M1激活具有重要意义。通过遗传学方法，我们发现MPC对于M1巨噬细胞的代谢重编程和激活是不可或缺的。此外，在内毒素血症小鼠模型中，骨髓细胞中MPC的缺失对炎症反应和巨噬细胞向M1表型的极化没有影响。虽然UK5099在约2-5 μM时达到最大的MPC抑制能力，但需要更高的浓度才能抑制M1中炎症细胞因子的产生，这与MPC表达无关。综上所述，MPC介导的代谢对于巨噬细胞的经典激活是必不可少的，UK5099抑制M1巨噬细胞的炎症反应是由于MPC抑制以外的作用。
Glycolysis is essential for the classical activation of macrophages (M1), but how glycolytic pathway metabolites engage in this process remains to be elucidated. Glycolysis leads to production of pyruvate, which can be transported into the mitochondria by the mitochondrial pyruvate carrier (MPC) followed by utilization in the tricarboxylic acid cycle. Based on studies that used the MPC inhibitor UK5099, the mitochondrial route has been considered to be of significance for M1 activation. Using genetic approaches, here we show that the MPC is dispensable for metabolic reprogramming and activation of M1 macrophages. In addition, MPC depletion in myeloid cells has no impact on inflammatory responses and macrophage polarization toward the M1 phenotype in a mouse model of endotoxemia. While UK5099 reaches maximal MPC inhibitory capacity at approximately 2–5 μM, higher concentrations are required to inhibit inflammatory cytokine production in M1 and this is independent of MPC expression. Taken together, MPC-mediated metabolism is dispensable for the classical activation of macrophages and UK5099 inhibits inflammatory responses in M1 macrophages due to effects other than MPC inhibition.