2. Academic Validation
  3. Metabolic reprogramming through histone lactylation in microglia and macrophages recruits CD8+ T lymphocytes and aggravates spinal cord injury

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

  • Neuron. 2025 Jul 23;113(14):2280-2296.e8. doi: 10.1016/j.neuron.2025.04.003.
Xuhui Ge 1,  Yufeng Zhu 2,  Junjun Xiong 2,  Yao Gu 2,  Xiaokun Wang 2,  Wu Ye 2,  Haofan Wang 2,  Yu Gao 2,  Weihua Cai 3,  Xuhui Zhou 4,  Wei Liu 5
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.
  • 3 Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China. Electronic address: caiwhspine@njmu.edu.cn.
  • 4 Department of Orthopedics, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China; Department of Stress Medicine, Faculty of Psychology, Naval Medical University, Shanghai 200433, China; Translational Research Centre of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China. Electronic address: zhouxuhui@smmu.edu.cn.
  • 5 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. Electronic address: liuweiorth@njmu.edu.cn.
PMID: 40328251 DOI: 10.1016/j.neuron.2025.04.003
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 CXCR6+CD8+ 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.

Keywords

CD8+ T lymphocytes; CXCL16; adaptive immunity; histone lactylation; metabolic reprogramming; microglia and macrophages.

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