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<p>Citrullinated histone H3 (CitH3), released from immune cells during early sepsis, drives a vicious cycle of inflammation through excessive NETosis and pyroptosis, causing immune dysfunction and tissue damage. To regulate this process, we develop a humanized CitH3 monoclonal antibody (hCitH3-mAb) with high affinity and specificity to target this process. In murine models, hCitH3-mAb reduces cytokine production, mortality and acute lung injury (ALI) caused by LPS and <i>Pseudomonas aeruginosa</i> while enhancing bacteria phagocytosis in the lungs, spleen, and liver. Using pre-equilibrium digital ELISA (PEdELISA), we identify an optimal therapeutic window for hCitH3-mAb in sepsis-induced ALI. In parallel, we explore the molecular mechanism underlying CitH3-driven inflammation. We find that in macrophages, CitH3 activates Toll-like receptor 2 (TLR2), triggering Ca<sup>2+</sup>-dependent PAD2 auto-citrullination and nuclear translocation, amplifying CitH3 production via a harmful feedback loop. The hCitH3-mAb treatment effectively disrupts this cycle and restores macrophage function under septic conditions. Together, these findings highlight both the therapeutic potential of hCitH3-mAb and provide a deep mechanistic insight into the CitH3–PAD2 axis in sepsis, supporting its further development for treating immune-mediated diseases.</p>

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A citrullinated histone H3 monoclonal antibody for immune modulation in sepsis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月12日

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  • Wenlu Ouyang,
  • Yuchen Chen,
  • Tao Tan,
  • Yujing Song,
  • Tao Dong,
  • Xin Yu,
  • Kyung Eun Lee,
  • Xinyu Zhou,
  • Zoe Tetz,
  • Sophia Go,
  • Xindi Zeng,
  • Liujiazi Shao,
  • Chao Quan,
  • Ting Zhao,
  • Yuzi Tian,
  • Katsuo Kurabayashi,
  • Hua Jin,
  • Jichun Ma,
  • Jingdong Qin,
  • Brandon Williams,
  • Qingtian Li,
  • Gui-dong Zhu,
  • Hasan B. Alam,
  • Kathleen A. Stringer,
  • Yongqing Li,
  • Jianjie Ma

摘要

Citrullinated histone H3 (CitH3), released from immune cells during early sepsis, drives a vicious cycle of inflammation through excessive NETosis and pyroptosis, causing immune dysfunction and tissue damage. To regulate this process, we develop a humanized CitH3 monoclonal antibody (hCitH3-mAb) with high affinity and specificity to target this process. In murine models, hCitH3-mAb reduces cytokine production, mortality and acute lung injury (ALI) caused by LPS and Pseudomonas aeruginosa while enhancing bacteria phagocytosis in the lungs, spleen, and liver. Using pre-equilibrium digital ELISA (PEdELISA), we identify an optimal therapeutic window for hCitH3-mAb in sepsis-induced ALI. In parallel, we explore the molecular mechanism underlying CitH3-driven inflammation. We find that in macrophages, CitH3 activates Toll-like receptor 2 (TLR2), triggering Ca2+-dependent PAD2 auto-citrullination and nuclear translocation, amplifying CitH3 production via a harmful feedback loop. The hCitH3-mAb treatment effectively disrupts this cycle and restores macrophage function under septic conditions. Together, these findings highlight both the therapeutic potential of hCitH3-mAb and provide a deep mechanistic insight into the CitH3–PAD2 axis in sepsis, supporting its further development for treating immune-mediated diseases.