Cathepsin C orchestrates RSV-induced asthma exacerbation through the dual effect of monocyte-derived macrophages

  • Cell Mol Immunol. 2026 Jun;23(6):719-733. doi: 10.1038/s41423-026-01423-w.
Xizi Du  1  2  3 ,  Xinyu Wu  2  4 ,  Lin Yuan  2  4 ,  Huaiqing Luo  5 ,  Leyuan Wang  2  6 ,  Huijun Liu  2  4 ,  Ye Yao  2  4 ,  Siqi Yao  2  4 ,  Qiuyan Qin  2  4 ,  Qianyu Zhao  2  4 ,  Dan Liu  7 ,  Yang Xiang  2  4 ,  Xiaoqun Qin  2  4 ,  Ming Yang  3 ,  Weining Xiong  8  9 ,  Chi Liu  10  11  12
Affiliations
  • 1. Department of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 2. Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, Hunan, China.
  • 3. Centre for Asthma and Respiratory Disease, School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, The University of Newcastle, and Hunter Medical Research Institute, Callaghan, NSW, Australia.
  • 4. Basic and Clinical Research Laboratory of Major Respiratory Diseases, Central South University, Changsha, Hunan, China.
  • 5. Department of Physiology, School of Basic Medical Sciences, Hunan Normal University, Changsha, Hunan, China.
  • 6. Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 7. Department of Pediatrics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China.
  • 8. Department of Pulmonary and Critical Care Medicine, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 9. Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 10. Department of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, China. [email protected].
  • 11. Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, Hunan, China. [email protected].
  • 12. Basic and Clinical Research Laboratory of Major Respiratory Diseases, Central South University, Changsha, Hunan, China. [email protected].
PMID: 42104048 DOI: 10.1038/s41423-026-01423-w
Abstract

Asthma exacerbations (AEs), especially those triggered by respiratory syncytial virus (RSV), remain clinically intractable because of limited treatment options and significant immune heterogeneity. In this study, we investigated the central cellular and molecular mechanisms driving RSV-induced AEs using a house dust mite-sensitized mouse model. Through macrophage depletion, transcriptomic profiling, and pathway inhibition, we identified monocyte-derived macrophages (Mo-Mφs) as key orchestrators of both Antiviral responses and inflammatory amplification. Mechanistically, Mo-Mφs upregulate and secrete Cathepsin C (CTSC), which in turn activates a previously unrecognized PR3/p38/RelB signaling axis. This axis established a positive feedback loop, sustaining macrophage activation and pathogenic inflammation. Pharmacological inhibition of CTSC disrupted this loop, leading to reduced lung inflammation, mucus hypersecretion, and airway hyperresponsiveness. However, this intervention was accompanied by a measurable compromise in Antiviral immunity. This study reveals a previously unrecognized CTSC-driven positive feedback loop in Mo-Mφs as a core pathogenic mechanism underlying RSV-induced AE. These findings identify CTSC as a promising mechanism-based therapeutic target, highlighting the need to carefully balance inflammation control against the preservation of Antiviral immunity.

Keywords
CTSC; RSV; asthma exacerbation; monocyte-derived macrophages.
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