Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, and Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, National Vaccine Innovation Platform, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Cell Rep. 2024 May 28;43(5):114180. doi: 10.1016/j.celrep.2024.114180. Epub 2024 May 10.
Macrophage activation is a hallmark of atherosclerosis, accompanied by a switch in core metabolism from oxidative phosphorylation to glycolysis. The crosstalk between metabolic rewiring and histone modifications in macrophages is worthy of further investigation. Here, we find that lactate efflux-associated monocarboxylate transporter 4 (MCT4)-mediated histone lactylation is closely related to atherosclerosis. Histone H3 lysine 18 lactylation dependent on MCT4 deficiency activated the transcription of anti-inflammatory genes and tricarboxylic acid cycle genes, resulting in the initiation of local repair and homeostasis. Strikingly, histone lactylation is characteristically involved in the stage-specific local repair process during M1 to M2 transformation, whereas histone methylation and acetylation are not. Gene manipulation and protein hydrolysis-targeted chimerism technology are used to confirm that MCT4 deficiency favors ameliorating atherosclerosis. Therefore, our study shows that macrophage MCT4 deficiency, which links metabolic rewiring and histone modifications, plays a key role in training macrophages to become repair and homeostasis phenotypes.
巨噬细胞的激活是动脉粥样硬化的一个标志，伴随着核心代谢从氧化磷酸化向糖酵解的转变。代谢重编程与巨噬细胞中组蛋白修饰之间的串扰值得进一步研究。在这里，我们发现与乳酸外排相关的单羧酸转运蛋白 4（MCT4）介导的组蛋白乳酰化与动脉粥样硬化密切相关。依赖于 MCT4 缺乏的组蛋白 H3 赖氨酸 18 乳酰化激活了抗炎基因和三羧酸循环基因的转录，从而启动了局部修复和动态平衡。引人注目的是，组蛋白乳酰化特征性地参与了 M1 向 M2 转化过程中的特定阶段的局部修复过程，而组蛋白甲基化和乙酰化则没有。基因操作和蛋白水解靶向嵌合体技术用于证实 MCT4 缺乏有利于改善动脉粥样硬化。因此，我们的研究表明，巨噬细胞 MCT4 缺乏，它将代谢重编程与组蛋白修饰联系起来，在训练巨噬细胞成为修复和动态平衡表型方面发挥着关键作用。
