Work

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

Year: 2025

Type: article

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. Eosinophils are involved in eosinophilic airway inflammation such as type 2 asthmatic responses. Here the authors investigate how lysosomes and cathepsin L affect the function and activation of eosinophils and that inhibition of cathepsin L reduces the pathology of allergic asthma in mice models.

Source: Nature Communications

DOI: 10.1038/s41467-025-65400-z