Role for Complement C5 in Eosinophilic Inflammation of Severe Asthma

  • Allergy. 2026 May;81(5):1571-1586. doi: 10.1111/all.16616.
Cong Dong  1 ,  Shaohua Lu  2 ,  Zhenan Deng  1 ,  Xuliang Cai  1 ,  Huahao Shen  3 ,  Guochao Shi  4 ,  Changxing Ou  1 ,  Zuofu Peng  5 ,  Wei Jiang  6 ,  Xiuhua Fu  7 ,  Changzheng Wang  8 ,  Meiling Jin  9 ,  Zhongmin Qiu  10 ,  Xiaoyang Wei  11 ,  Wei Gu  12 ,  Kewu Huang  13 ,  Qiang Li  14 ,  Xiangyan Zhang  15 ,  Nanshan Zhong  1 ,  Kian Fan Chung  16 ,  Qingling Zhang  1 ,  C‐BIOPRED Consortium
Affiliations
  • 1. State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 2. Sino-French Hoffmann Institute, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.
  • 3. Department of Respiratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
  • 4. Department of Respiratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 5. Alpha X(Beijing) Biotech CO., Beijing, China.
  • 6. AstraZeneca, Shanghai Shi, China.
  • 7. Department of Respiratory Medicine, The Affiliated Hospital of Inner Mongolia Medical University, Huhhot, China.
  • 8. Department of Respiratory Medicine, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 9. Department of Respiratory Medicine, Zhongshan Hospital, Shanghai, China.
  • 10. Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 11. Department of Respiratory Medicine, The Eighth Medical Center of PLA General Hospital, Beijing, China.
  • 12. Department of Respiratory, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
  • 13. Department of Respiratory Medicine, Beijing Chao-Yang Hospital, Beijing, China.
  • 14. Department of Respiratory Medicine, Shanghai General Hospital, Shanghai, China.
  • 15. Department of Respiratory Medicine, Guizhou Province People's Hospital, Guiyang, China.
  • 16. National Heart and Lung Institute, Imperial College London, & Royal Brompton & Harefield Hospital, London, UK.
PMID: 40524528 DOI: 10.1111/all.16616
Abstract

Background: We investigated the role of the Complement System, particularly complement C5, in severe asthma defined from an analysis of sputum proteomics. Although there has been evidence of complement activation in asthma, its role in severe asthma remains unclear.

Method: Sputum protein expression profiles were analyzed from healthy controls and severe asthma patients using data-dependent acquisition mass spectrometry. Weighted correlation network analysis (WGCNA) was used to define the unique modules that were highly correlated with clinical, physiologic, and inflammatory traits. Differential analysis was performed for the complement C5 pathway protein levels and eosinophilic protein expression as influenced by C5. Asthmatic mouse models were used to verify the effect of complement C5 administration and inhibition.

Results: The WGCNA "brown" module related to the Complement System activation was positively correlated with eosinophilic inflammation. Specifically, C5 and downstream complement proteins were up-regulated in patients with high sputum eosinophil levels (≥ 3%) compared to low sputum eosinophils (< 3%). Patients with reduced C5 expression had less eosinophilic inflammation and better lung function. Using single-cell RNA Sequencing and immunofluorescence staining led to identification of macrophages as the main source of C5. In vivo experiments confirmed that inhibiting C5 reduced inflammation in allergic mouse models, while direct stimulation with recombinant C5 in IL-5 transgenic mice increased eosinophilic inflammation.

Conclusion: We demonstrate a direct role for complement C5 in exacerbating eosinophilic inflammation in severe asthma.

Keywords
C5aR1; C5aR2; complement C5; complement C5 receptors; eosinophilic inflammation; severe asthma; weighted correlation network analysis.
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