He Lu, Yin Rui, Hang Weijian, Han Jinli, Chen Juan, Wen Bin, Chen Ling
Division of Neonatology, Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Biomedicines. 2024 Oct 17;12(10):2371. doi: 10.3390/biomedicines12102371.
Hypoxia-induced M1 polarization of microglia and resultant inflammation take part in the damage caused by hypoxic-ischemic encephalopathy (HIE). Histone lactylation, a novel epigenetic modification where lactate is added to lysine residues, may play a role in HIE pathogenesis. This study investigates the role of histone lactylation in hypoxia-induced M1 microglial polarization and inflammation, aiming to provide insights for HIE treatment.
In this study, we assessed the effects of hypoxia on microglial polarization using both an HIE animal model and an oxygen-glucose deprivation cell model. Histone lactylation at various lysine residues was detected by Western blotting. Microglial polarization and inflammatory cytokines were analyzed by immunofluorescence, qPCR, and Western blotting. RNA sequencing, ChIP-qPCR, and siRNA were used to elucidate mechanisms of H3K9 lactylation.
H3K9 lactylation increased due to cytoplasmic lactate during M1 polarization. Inhibiting P300 or reducing lactate dehydrogenase A expression decreased H3K9 lactylation, suppressing M1 polarization. Transcriptomic analysis indicated that H3K9 lactylation regulated M1 polarization via the TNF signaling pathway. ChIP-qPCR confirmed H3K9 lactylation enrichment at the TNFα locus, promoting OGD-induced M1 polarization and inflammation.
H3K9 lactylation promotes M1 polarization and inflammation via the TNF pathway, identifying it as a potential therapeutic target for neonatal HIE.
缺氧诱导的小胶质细胞M1极化及由此产生的炎症参与了缺氧缺血性脑病（HIE）所致的损伤。组蛋白乳酸化是一种新的表观遗传修饰，即乳酸添加到赖氨酸残基上，可能在HIE发病机制中起作用。本研究探讨组蛋白乳酸化在缺氧诱导的小胶质细胞M1极化和炎症中的作用，旨在为HIE治疗提供思路。
在本研究中，我们使用HIE动物模型和氧糖剥夺细胞模型评估缺氧对小胶质细胞极化的影响。通过蛋白质免疫印迹法检测各种赖氨酸残基处的组蛋白乳酸化。通过免疫荧光、qPCR和蛋白质免疫印迹法分析小胶质细胞极化和炎性细胞因子。使用RNA测序、染色质免疫沉淀-qPCR和小干扰RNA来阐明H3K9乳酸化的机制。
在M1极化过程中，由于细胞质乳酸增加，H3K9乳酸化增加。抑制P300或降低乳酸脱氢酶A表达可降低H3K9乳酸化，抑制M1极化。转录组分析表明，H3K9乳酸化通过TNF信号通路调节M1极化。染色质免疫沉淀-qPCR证实TNFα基因座处H3K9乳酸化富集，促进氧糖剥夺诱导的M1极化和炎症。
H3K9乳酸化通过TNF途径促进M1极化和炎症，将其确定为新生儿HIE的潜在治疗靶点。
