Synergistic inhibition of CitH3 and S100A8/A9: A novel therapeutic strategy for mitigating sepsis-induced inflammation and lung injury

  • Int J Immunopathol Pharmacol. 2025 Jan-Dec:39:3946320251338661. doi: 10.1177/03946320251338661.
Tao Dong  1  2 ,  Wenlu Ouyang  1  3 ,  Xin Yu  1  4 ,  Ting Zhao  5 ,  Liujiazi Shao  1  6 ,  Chao Quan  1  7 ,  Suhe Wang  8 ,  Jianjie Ma  9 ,  Yongqing Li  1
Affiliations
  • 1. Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA.
  • 2. Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 3. Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China.
  • 4. Department of Emergency Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 5. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 6. Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
  • 7. Department of Urology, The Xiangya Hospital, Central South University, Changsha, China.
  • 8. Internal Medicine, Division of Allergy, University of Michigan Health System, Ann Arbor, MI, USA.
  • 9. Department of Surgery, Division of Surgical Science, University of Virginia, Charlottesville, VA, USA.
PMID: 40390290 DOI: 10.1177/03946320251338661
Abstract

Objective: Sepsis is a life-threatening condition with high global morbidity and mortality. Citrullinated histone H3 (CitH3) has gained recognition as a significant biomarker for early sepsis diagnosis and management. This study aims to investigate the therapeutic potential of targeting both CitH3 and S100A8/A9 to reduce sepsis-induced inflammation and organ damage.

Methods: Using a novel CitH3 antibody distinct from commercial options, we analyzed serum samples from LPS-treated mice through a co-immunoprecipitation assay followed by LC-MS/MS proteomic analysis to explore the interaction between CitH3 and S100A8/A9 proteins in peripheral blood. Additionally, in a Pseudomonas aeruginosa (PA)-induced lung injury model, we assessed CitH3 and S100A8/A9 levels in bronchoalveolar lavage fluid (BALF), alveolar samples, and neutrophils to determine their influence on neutrophil activation and inflammatory responses.

Results: Our study revealed, for the first time, that CitH3 and S100A8/A9 synergistically promoted neutrophil activation, inflammatory responses, and NETosis, which exacerbated lung injury in sepsis. Dual targeting of CitH3 and S100A8/A9 significantly reduced neutrophil recruitment, NETosis, and inflammation in the PA-induced lung injury model. This therapeutic approach improved lung injury and survival rates, accompanied by a shift in cytokine profiles, with reductions in pro-inflammatory cytokines and increases in anti-inflammatory cytokines.

Conclusion: These findings underscore the potential of dual targeting CitH3 and S100A8/A9 as a novel therapeutic approach for sepsis. This combined intervention shows promising effects in reducing inflammation and enhancing survival, offering a groundbreaking strategy for sepsis diagnosis and treatment.

Keywords
CitH3; NETosis; S100A8/A9; hCitH3-mAb; sepsis; survival.
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