A citrullinated histone H3 monoclonal antibody for immune modulation in sepsis
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 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.
Authors
- Xinyu Zhou (ORCID: https://orcid.org/0000-0002-2045-7695)
- Brandon Williams (ORCID: https://orcid.org/0000-0001-9517-2531)
- Kathleen A. Stringer (ORCID: https://orcid.org/0000-0003-0238-7774)
- Yujing Song (ORCID: https://orcid.org/0000-0003-1448-3069)
- Katsuo Kurabayashi (ORCID: https://orcid.org/0000-0002-9613-3590)
- Liu-Jia-Zi Shao
- Tao Tan (ORCID: https://orcid.org/0009-0003-3973-9929)
- Hasan B. Alam (ORCID: https://orcid.org/0000-0002-1024-5226)
- Seok Hyeon Go
- Jingdong Qin
- Xiaofeng Zeng (ORCID: https://orcid.org/0000-0002-3883-2318)
- Yuzi Tian (ORCID: https://orcid.org/0000-0001-5267-2456)
- Hua Jin (ORCID: https://orcid.org/0000-0001-5478-4611)
- Zoe Tetz (ORCID: https://orcid.org/0009-0004-7853-6443)
- Kyung Eun Lee (ORCID: https://orcid.org/0000-0002-9535-7314)
- Yuchen Chen (ORCID: https://orcid.org/0000-0001-8558-3062)
- Yongqing Li (ORCID: https://orcid.org/0000-0001-8266-924X)
- Qingtian Li (ORCID: https://orcid.org/0000-0003-1170-0806)
- Chao Quan (ORCID: https://orcid.org/0000-0003-1040-3930)
- Jichun Ma (ORCID: https://orcid.org/0000-0002-9617-5141)
- Ting C. Zhao (ORCID: https://orcid.org/0009-0004-0768-4764)
- Jianjie Ma
- Gui‐Dong Zhu
- Tao Dong
- Xin Yu
- Wenlu Ouyang
Institutions
- Northwestern University (US)
- Harvard University (US)
- Central South University (CN)
- Xuzhou Medical College (CN)
- University of Michigan (US)
- Society of Critical Care Medicine (US)
- Massachusetts General Hospital (US)
- Michigan Medicine (US)
- Second Xiangya Hospital of Central South University (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Xiangya Hospital Central South University (CN)
- University of Virginia (US)
- New York University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-12
- DOI
- https://doi.org/10.1038/s41467-025-62788-6
- Citations
- 9
- Primary Topic
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 7.18
Funders
- National Institutes of Health
- National Institute of General Medical Sciences