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

IF 9.3 1区医学 Q1 IMMUNOLOGY Journal of Neuroinflammation Pub Date : 2024-08-03 DOI:10.1186/s12974-024-03186-5

Xuyang Hu, Jinxin Huang, Ziyu Li, Jianjian Li, Fangru Ouyang, Zeqiang Chen, Yiteng Li, Yuanzhe Zhao, Jingwen Wang, Shuisheng Yu, Juehua Jing, Li Cheng

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Abstract

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.

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乳酸可促进小胶质细胞瘢痕的形成，并通过增强脊髓损伤后组蛋白 H4 赖氨酸 12 的乳化作用促进运动功能的恢复。

乳酸衍生的组蛋白乳酰化通过转录调控参与多种病理过程。乳酸衍生的组蛋白乳酸化在脊髓损伤（SCI）修复中的作用仍不清楚。在这里，我们报告了脊髓损伤后脊髓中整体乳酸水平和乳酸化上调的情况。值得注意的是，在损伤脊髓的小胶质细胞中，H4K12la明显升高，而外源乳酸盐处理进一步升高了SCI后小胶质细胞中的H4K12la。在功能上，乳酸盐处理促进了损伤脊髓后小胶质细胞的增殖、瘢痕形成、轴突再生和运动功能的恢复。从机制上讲，乳酸盐介导的 H4K12la 升高促进了小胶质细胞中 PD-1 的转录，从而促进了 SCI 的修复。此外，一系列抢救实验证实，PD-1抑制剂或小胶质细胞特异性AAV-sh-PD-1能显著逆转乳酸盐在SCI后的治疗效果。这项研究说明了乳酸/H4K12la/PD-1 信号在小胶质细胞介导的组织修复中的功能和机制，并为 SCI 治疗提供了一个新靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Neuroinflammation 医学-神经科学

CiteScore

15.90

自引率

3.20%

发文量

276

审稿时长

1 months

期刊介绍： The Journal of Neuroinflammation is a peer-reviewed, open access publication that emphasizes the interaction between the immune system, particularly the innate immune system, and the nervous system. It covers various aspects, including the involvement of CNS immune mediators like microglia and astrocytes, the cytokines and chemokines they produce, and the influence of peripheral neuro-immune interactions, T cells, monocytes, complement proteins, acute phase proteins, oxidative injury, and related molecular processes. Neuroinflammation is a rapidly expanding field that has significantly enhanced our knowledge of chronic neurological diseases. It attracts researchers from diverse disciplines such as pathology, biochemistry, molecular biology, genetics, clinical medicine, and epidemiology. Substantial contributions to this field have been made through studies involving populations, patients, postmortem tissues, animal models, and in vitro systems. The Journal of Neuroinflammation consolidates research that centers around common pathogenic processes. It serves as a platform for integrative reviews and commentaries in this field.