Lactate promotes microglial scar formation and facilitates locomotor function recovery by enhancing histone H4 lysine 12 lactylation after spinal cord injury

被引：19

作者：

Hu, Xuyang ^{[1
,2
]}

Huang, Jinxin ^{[1
,2
]}

Li, Ziyu ^{[1
,2
]}

Li, Jianjian ^{[1
,2
]}

Ouyang, Fangru ^{[1
,2
]}

Chen, Zeqiang ^{[1
,2
]}

Li, Yiteng ^{[1
,2
]}

Zhao, Yuanzhe ^{[1
,2
]}

Wang, Jingwen ^{[1
,2
]}

Yu, Shuisheng ^{[1
,2
]}

Jing, Juehua ^{[1
,2
]}

Cheng, Li ^{[1
,2
]}

机构：

[1] Anhui Med Univ, Dept Orthopaed, Affiliated Hosp 2, 678 Furong Rd, Hefei 230601, Peoples R China

[2] Anhui Med Univ, Inst Orthopaed, Res Ctr Translat Med, Affiliated Hosp 2, Hefei 230601, Anhui, Peoples R China

来源：

JOURNAL OF NEUROINFLAMMATION | 2024年 / 21卷 / 01期

关键词：

Spinal cord injury; Microglia; Lactate; PD-1; METABOLIC-REGULATION; GENE-EXPRESSION; GLIAL SCAR; BRAIN; REGENERATION; ASTROCYTES; DEPENDENCE; EFFICACY; GROWTH;

D O I：

10.1186/s12974-024-03186-5

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Lactate-derived histone lactylation is involved in multiple pathological processes through transcriptional regulation. The role of lactate-derived histone lactylation in the repair of spinal cord injury (SCI) remains unclear. Here we report that overall lactate levels and lactylation are upregulated in the spinal cord after SCI. Notably, H4K12la was significantly elevated in the microglia of the injured spinal cord, whereas exogenous lactate treatment further elevated H4K12la in microglia after SCI. Functionally, lactate treatment promoted microglial proliferation, scar formation, axon regeneration, and locomotor function recovery after SCI. Mechanically, lactate-mediated H4K12la elevation promoted PD-1 transcription in microglia, thereby facilitating SCI repair. Furthermore, a series of rescue experiments confirmed that a PD-1 inhibitor or microglia-specific AAV-sh-PD-1 significantly reversed the therapeutic effects of lactate following SCI. This study illustrates the function and mechanism of lactate/H4K12la/PD-1 signaling in microglia-mediated tissue repair and provides a novel target for SCI therapy.

引用

页数：23

共 73 条

[1] The Neuroprotective Effect of Lactate Is Not Due to Improved Glutamate Uptake after Controlled Cortical Impact in Rats [J].