A citrullinated histone H3 monoclonal antibody for immune modulation in sepsis

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 () and Jianjie Ma ()
Additional contact information
Wenlu Ouyang: University of Michigan Health System
Yuchen Chen: University of Virginia
Tao Tan: University of Virginia
Yujing Song: NYU Tandon School of Engineering
Tao Dong: University of Michigan Health System
Xin Yu: University of Michigan Health System
Kyung Eun Lee: University of Virginia
Xinyu Zhou: University of Virginia
Zoe Tetz: University of Virginia
Sophia Go: University of Virginia
Xindi Zeng: University of Virginia
Liujiazi Shao: University of Michigan Health System
Chao Quan: University of Michigan Health System
Ting Zhao: Harvard Medical School
Yuzi Tian: University of Michigan Health System
Katsuo Kurabayashi: NYU Tandon School of Engineering
Hua Jin: SparX Biopharmaceutical Corp
Jichun Ma: SparX Biopharmaceutical Corp
Jingdong Qin: SparX Biopharmaceutical Corp
Brandon Williams: SparX Biopharmaceutical Corp
Qingtian Li: SparX Biopharmaceutical Corp
Gui-dong Zhu: SparX Biopharmaceutical Corp
Hasan B. Alam: Arkes Pavilion
Kathleen A. Stringer: University of Michigan
Yongqing Li: University of Michigan Health System
Jianjie Ma: University of Virginia

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62788-6

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