小胶质细胞和巨噬细胞中通过组蛋白乳酰化进行的代谢重编程会募集CD8 T淋巴细胞并加重脊髓损伤。

Metabolic reprogramming through histone lactylation in microglia and macrophages recruits CD8 T lymphocytes and aggravates spinal cord injury.

作者信息

Ge Xuhui, Zhu Yufeng, Xiong Junjun, Gu Yao, Wang Xiaokun, Ye Wu, Wang Haofan, Gao Yu, Cai Weihua, Zhou Xuhui, Liu Wei

机构信息

Department of Orthopedics, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China; Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China; Department of Stress Medicine, Faculty of Psychology, Naval Medical University, Shanghai 200433, China.

Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.

出版信息

Neuron. 2025 Apr 24. doi: 10.1016/j.neuron.2025.04.003.

DOI:10.1016/j.neuron.2025.04.003

PMID:40328251

Abstract

Crosstalk between the central nervous system (CNS) and the immune system has recently gained increased attention; however, the interaction between innate and adaptive immunity after CNS injury remains unclear. Here, using single-cell RNA sequencing, we identified accumulation of CD8 T lymphocytes in the cerebrospinal fluid of patients with spinal cord injury (SCI) and in spinal cords of injured mice, thus indicating poor neurological function. Furthermore, through genetic or pharmacologic interruption strategies, we found that CXCL16 chemokines derived from injury-activated microglia and macrophages (IAMs) recruited CXCR6CD8 T cells and further contributed to neuronal loss after SCI. Mechanistically, glycolytic reprogramming in IAMs enhanced histone-lactylation-mediated Cxcl16 transcription, whereas suppressing glycolysis through Pkm2 deletion partially reversed this effect. Notably, a pharmacologic intervention targeting the CXCL16-CXCR6 axis with Rutin promoted locomotor restoration after SCI. Our study highlights the crucial role of glycolytically reprogrammed IAM-derived CXCL16 chemokines in modulating a maladaptive innate/adaptive immune axis and reveals several potential therapeutic strategies.

摘要

中枢神经系统（CNS）与免疫系统之间的相互作用近来受到了更多关注；然而，中枢神经系统损伤后固有免疫和适应性免疫之间的相互作用仍不清楚。在此，我们通过单细胞RNA测序发现，脊髓损伤（SCI）患者的脑脊液以及受伤小鼠的脊髓中存在CD8 T淋巴细胞积聚，这表明神经功能较差。此外，通过基因或药物阻断策略，我们发现损伤激活的小胶质细胞和巨噬细胞（IAMs）产生的CXCL16趋化因子招募了CXCR6⁺ CD8 T细胞，并进一步导致脊髓损伤后神经元丢失。机制上，IAMs中的糖酵解重编程增强了组蛋白乳酸化介导的Cxcl16转录，而通过敲除Pkm2抑制糖酵解可部分逆转这一效应。值得注意的是，用芦丁靶向CXCL16 - CXCR6轴的药物干预促进了脊髓损伤后的运动功能恢复。我们的研究突出了糖酵解重编程的IAM来源的CXCL16趋化因子在调节适应性不良的固有/适应性免疫轴中的关键作用，并揭示了几种潜在的治疗策略。