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<p>Elevated lactate levels are a hallmark of severe infections and are associated with poor outcomes in sepsis patients, but the underlying mechanisms remain poorly understood. Recent findings have shown that lactate can covalently modify histones (e.g., histone lactylation) in macrophages, acting as a critical epigenetic regulator of inflammatory response. Here, we demonstrate that histone lactylation also occurs in neutrophils—the first immune cells mobilized during acute inflammation—and is functionally important for their activation. Using both DMSO-differentiated HL-60 (dHL-60) cells and primary neutrophils, we found that LPS stimulation significantly increased intracellular lactate levels and histone lactylation, particularly at the H4K8 site. These changes enhanced cytokine release, ROS production, and chemotaxis. Lactate further amplified these effects, while inhibition of glycolysis or p300 suppressed them. Multi-omics analyses revealed substantial enrichment of H4K8la at the promoter region of <i>WTAP</i>, a key m<sup>6</sup>A methyltransferase component, promoting its expression via CEBP/β recruitment. <i>WTAP</i> knockdown significantly reduced m<sup>6</sup>A modifications of <i>TLR2</i> mRNA and impaired its stability. Both <i>WTAP</i> knockdown and TLR2 inhibition markedly dampened the inflammatory responses. Importantly, this glycolysis-H4K8la-WTAP-TLR2 axis was further validated in LPS-induced septic mice and pediatric sepsis patients, highlighting its clinical relevance. In summary, our findings uncover a novel lactate-driven epigenetic—post-transcriptional regulatory circuit that amplifies neutrophil inflammatory responses, expanding the regulatory framework of innate immunity and providing potential therapeutic targets for hyperinflammation.</p>

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Upregulation of m6A writer WTAP by histone lactylation promotes inflammatory response via TLR2 in neutrophils

  • 期刊论文

  • 发表日期：

    2026年1月14日

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  • Bailu Du,
  • Wenting Song,
  • Yiming Zhang,
  • Yan Yin,
  • Yuanjie Zhou,
  • Yi Pan,
  • Ruwen Yang,
  • Muxiu Jiang,
  • Nan Shen,
  • Qihua Fu,
  • Jianye Zang,
  • Yue Tao,
  • Xi Mo

摘要

Elevated lactate levels are a hallmark of severe infections and are associated with poor outcomes in sepsis patients, but the underlying mechanisms remain poorly understood. Recent findings have shown that lactate can covalently modify histones (e.g., histone lactylation) in macrophages, acting as a critical epigenetic regulator of inflammatory response. Here, we demonstrate that histone lactylation also occurs in neutrophils—the first immune cells mobilized during acute inflammation—and is functionally important for their activation. Using both DMSO-differentiated HL-60 (dHL-60) cells and primary neutrophils, we found that LPS stimulation significantly increased intracellular lactate levels and histone lactylation, particularly at the H4K8 site. These changes enhanced cytokine release, ROS production, and chemotaxis. Lactate further amplified these effects, while inhibition of glycolysis or p300 suppressed them. Multi-omics analyses revealed substantial enrichment of H4K8la at the promoter region of WTAP, a key m6A methyltransferase component, promoting its expression via CEBP/β recruitment. WTAP knockdown significantly reduced m6A modifications of TLR2 mRNA and impaired its stability. Both WTAP knockdown and TLR2 inhibition markedly dampened the inflammatory responses. Importantly, this glycolysis-H4K8la-WTAP-TLR2 axis was further validated in LPS-induced septic mice and pediatric sepsis patients, highlighting its clinical relevance. In summary, our findings uncover a novel lactate-driven epigenetic—post-transcriptional regulatory circuit that amplifies neutrophil inflammatory responses, expanding the regulatory framework of innate immunity and providing potential therapeutic targets for hyperinflammation.