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<p>Microglial functional plasticity is shaped by metabolic and epigenetic reprogramming, but how these processes regulate central nervous system autoimmunity remains unclear. We find that cerebrospinal fluid lactate levels correlate with multiple sclerosis severity. Using female mouse models of experimental autoimmune encephalomyelitis, spinal lactate accumulation drives persistent microglial histone lactylation, coupling to glycolytic activation. Microglia-specific deletion of lactate dehydrogenase A reduces this lactylation and exacerbates disease severity. Exogenous lactate ameliorates pathology without altering peripheral immune infiltration by suppressing inflammatory states and promoting reparative programs. Epigenomic profiling demonstrates direct lactylation enrichment at promoters of neurotrophic genes, linking metabolic flux to transcriptional activation. Histone deacetylase 1 acts as an epigenetic brake by erasing this modification; its inhibition restores neurotrophic signaling and mitigates pathology. In this work, we show that a lactate-driven epigenetic axis governs microglial state transitions, highlighting a tractable therapeutic target for metabolic intervention in neuroinflammatory diseases.</p>

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A Lactate–H4K12la–HDAC1 epigenetic axis governs microglial state transitions during experimental autoimmune encephalomyelitis in female mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月4日

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  • Jiahong Li,
  • Su Meng,
  • Jiajian Li,
  • Quanfeng Wei,
  • Xin Hua,
  • Jinzhou Feng,
  • WenYu Hu,
  • Hongxing Wang,
  • Yinan Zhao

摘要

Microglial functional plasticity is shaped by metabolic and epigenetic reprogramming, but how these processes regulate central nervous system autoimmunity remains unclear. We find that cerebrospinal fluid lactate levels correlate with multiple sclerosis severity. Using female mouse models of experimental autoimmune encephalomyelitis, spinal lactate accumulation drives persistent microglial histone lactylation, coupling to glycolytic activation. Microglia-specific deletion of lactate dehydrogenase A reduces this lactylation and exacerbates disease severity. Exogenous lactate ameliorates pathology without altering peripheral immune infiltration by suppressing inflammatory states and promoting reparative programs. Epigenomic profiling demonstrates direct lactylation enrichment at promoters of neurotrophic genes, linking metabolic flux to transcriptional activation. Histone deacetylase 1 acts as an epigenetic brake by erasing this modification; its inhibition restores neurotrophic signaling and mitigates pathology. In this work, we show that a lactate-driven epigenetic axis governs microglial state transitions, highlighting a tractable therapeutic target for metabolic intervention in neuroinflammatory diseases.