Lysosomal acidity and cathepsin L activate eosinophils via ARG1-mediated arginine metabolism in allergic airway inflammation

Yinling Han, Na Li, Yun Zhao, Zhangchu Jin, Baihui Lv, Dan Shen, Xinyi Chen, Qingyu Weng, Min Zhang, Kaijun Chen, Lingling Dong, Zhengyuan Liu, Jiafei Lou, Shenwei Gao, Yuejue Wang, Wen Hua, Fugui Yan, Songmin Ying, Yinfang Wu (), Zhihua Chen () and Wen Li ()
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Yinling Han: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Na Li: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Yun Zhao: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Zhangchu Jin: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Baihui Lv: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Dan Shen: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Xinyi Chen: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Qingyu Weng: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Min Zhang: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Kaijun Chen: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Lingling Dong: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Zhengyuan Liu: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Jiafei Lou: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Shenwei Gao: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Yuejue Wang: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Wen Hua: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Fugui Yan: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Songmin Ying: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Yinfang Wu: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Zhihua Chen: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine
Wen Li: Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Eosinophils are the predominant immune cells implicated in the pathogenesis of asthma, highlighting the need for strategies to mitigate their effects. While previous studies have implicated the importance of lysosomes in eosinophil function, the precise role of lysosomes in eosinophil activation during asthma remains insufficiently understood. In this study, we demonstrate that lysosomal acidity and cathepsin L activity in eosinophils are elevated in asthmatic patients and mouse models. Genetic deletion or pharmacological inhibition of cathepsin L in eosinophils attenuates allergic airway inflammation in vivo and suppresses eosinophil activation in vitro. Cathepsin L in eosinophils promotes type 2 immune responses by upregulating arginase 1 expression and interacting with it, thereby enhancing arginase 1 activity and altering arginine metabolism during eosinophil activation. This metabolic shift leads to increased production of ornithine, which exacerbates inflammatory processes. Furthermore, lysosomal acidity and cathepsin L activity correlate with disease severity in asthmatic patients. Our findings implicate that lysosomal acidity and cathepsin L facilitate eosinophil activation through arginine metabolism, thereby promoting allergic airway inflammation.

Date: 2025
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DOI: 10.1038/s41467-025-65400-z

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