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<p>Trained immunity refers to the long-term memory of the innate immune cells. However, little is known about how environmental nutrient availability influences trained immunity. This study finds that physiologic carbon sources impact glucose contribution to the tricarboxylic acid (TCA) cycle and enhance cytokine production of trained monocytes. Our experiments demonstrate that trained monocytes preferentially employe lactate over glucose as a TCA cycle substrate, and lactate metabolism is required for trained immune cell responses to bacterial and fungal infection. Except for the contribution to the TCA cycle, endogenous lactate or exogenous lactate also supports trained immunity by regulating histone lactylation. Further transcriptome analysis, ATAC-seq, and CUT&amp;Tag-seq demonstrate that lactate enhance chromatin accessibility in a manner dependent histone lactylation. Inhibiting lactate-dependent metabolism by silencing lactate dehydrogenase A (LDHA) impairs both lactate fueled the TCA cycle and histone lactylation. These findings suggest that lactate is the hub of immunometabolic and epigenetic programs in trained immunity.</p>

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Lactate activates trained immunity by fueling the tricarboxylic acid cycle and regulating histone lactylation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月4日

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  • Huanhuan Cai,
  • Xueyuan Chen,
  • Yan Liu,
  • Yingbo Chen,
  • Gechang Zhong,
  • Xiaoyu Chen,
  • Shuo Rong,
  • Hao Zeng,
  • Lin Zhang,
  • Zelong Li,
  • Aihua Liao,
  • Xiangtai Zeng,
  • Wei Xiong,
  • Cihang Guo,
  • Yanfang Zhu,
  • Ke-Qiong Deng,
  • Hong Ren,
  • Huan Yan,
  • Zeng Cai,
  • Ke Xu,
  • Li Zhou,
  • Zhibing Lu,
  • Fubing Wang,
  • Shi Liu

摘要

Trained immunity refers to the long-term memory of the innate immune cells. However, little is known about how environmental nutrient availability influences trained immunity. This study finds that physiologic carbon sources impact glucose contribution to the tricarboxylic acid (TCA) cycle and enhance cytokine production of trained monocytes. Our experiments demonstrate that trained monocytes preferentially employe lactate over glucose as a TCA cycle substrate, and lactate metabolism is required for trained immune cell responses to bacterial and fungal infection. Except for the contribution to the TCA cycle, endogenous lactate or exogenous lactate also supports trained immunity by regulating histone lactylation. Further transcriptome analysis, ATAC-seq, and CUT&Tag-seq demonstrate that lactate enhance chromatin accessibility in a manner dependent histone lactylation. Inhibiting lactate-dependent metabolism by silencing lactate dehydrogenase A (LDHA) impairs both lactate fueled the TCA cycle and histone lactylation. These findings suggest that lactate is the hub of immunometabolic and epigenetic programs in trained immunity.