Lactate induces tumor-associated macrophage polarization independent of mitochondrial pyruvate carrier-mediated metabolism
Lactate induces tumor-associated macrophage polarization independent of mitochondrial pyruvate carrier-mediated metabolism
复制标题
DOI：
10.1016/j.ijbiomac.2023.123810
复制
发表时间：
2023-03-30
影响因子：
8.2
通讯作者：
Wang, Feilong
中科院分区：
文献类型：
--
作者：
Fang, Xia;Zhao, Pei;Wang, Feilong
肿瘤细胞来源的乳酸被认为是肿瘤相关巨噬细胞(TAMs)极化的关键驱动因素。在线粒体丙酮酸载体(MPC)的介导下，肿瘤内的乳酸可以转运到巨噬细胞内，为TCA循环提供能量。在细胞内代谢的核心，MPC介导的转运已经被研究表明它在TAMS的分化过程中的作用和重要性。然而，以前的研究依赖于药物抑制而不是遗传方法来评估MPC在TAMS极化中的作用。在这里，我们证明了MPC的遗传耗竭阻止了乳酸进入巨噬细胞的线粒体。然而，MPC介导的代谢对于IL-4/乳酸诱导的巨噬细胞极化和肿瘤生长是必不可少的。此外，MPC的缺失对TAMS极化所必需的缺氧诱导因子1α(HIF-1α)的稳定和组蛋白乳糖化没有影响。我们的研究表明，乳酸盐本身，而不是其下游的代谢物，是TAMS极化的原因。
Tumor cell-derived lactate has been recognized as the key driver of polarization in tumor-associated macro-phages (TAMs). Intratumoral lactate can be transported into macrophages to fuel the TCA cycle, which is mediated by mitochondrial pyruvate carrier (MPC). At the heart of intracellular metabolism, MPC-mediated transport has been investigated in studies which suggested its role and importance in the process of TAMs po-larization. However, previous studies relied on pharmacological inhibition instead of genetic approaches to evaluate the role of MPC in TAMs polarization. Here, we demonstrated that genetic depletion of MPC blocks the entry of lactate into mitochondria in macrophages. However, MPC-mediated metabolism was dispensable for IL-4/lactate-induced macrophages polarization as well as tumor growth. In addition, MPC depletion had no impact on hypoxia-inducible factor 1 alpha (HIF-1 alpha) stabilization and histone lactylation, both of which are required for TAMs polarization. Our study suggests that lactate itself, rather than its downstream metabolites, is responsible for TAMs polarization.