Macrophage MCT4 inhibition activates reparative genes and protects from atherosclerosis by histone H3 lysine 18 lactylation

• Published in: Cell reports (Cambridge) Vol. 43; no. 5; p. 114180
• Main Authors: Zhang, Yunjia, Jiang, Hong, Dong, Mengdie, Min, Jiao, He, Xian, Tan, Yongkang, Liu, Fuhao, Chen, Minghong, Chen, Xiang, Yin, Quanwen, Zheng, Longbin, Shao, Yongfeng, Li, Xuesong, Chen, Hongshan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.05.2024; Elsevier
• Subjects: Animals; atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; CP: Molecular biology; histone lactylation; Histones - metabolism; Humans; inflammatory; Lysine - metabolism; macrophage; Macrophage Activation; Macrophages - metabolism; MCT4; Mice; Mice, Inbred C57BL; Monocarboxylic Acid Transporters - genetics; Monocarboxylic Acid Transporters - metabolism; Muscle Proteins - genetics; Muscle Proteins - metabolism; tissue repair; atherosclerosis; MCT4; histone lactylation; inflammatory; CP: Molecular biology; macrophage; tissue repair
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114180

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. [Display omitted] •MCT4 is highly expressed in macrophages of atherosclerotic plaque•Macrophage MCT4 deficiency enhances p300-mediated histone lactylation•H3K18la initiates macrophage repair and promotes inflammatory resolution Zhang et al. show that MCT4 deficiency can enhance H3K18la level, which favors a reparative environment through improving anti-inflammatory activity and metabolic rewiring. They also show that administration of MCT4 inhibitors decreases atherosclerosis progression, demonstrating the therapeutic potential of MCT4 inhibitors in atherosclerosis.