溶酶体酸度与组织蛋白酶L通过ARG1介导的精氨酸代谢激活嗜酸性粒细胞参与过敏性气道炎症
2025/12/30
摘要：
嗜酸性粒细胞是哮喘发病机制中最重要的免疫细胞，因此亟需寻找减轻其作用的策略。尽管已有研究提示溶酶体在嗜酸性粒细胞功能中具有重要作用，但其在哮喘过程中对嗜酸性粒细胞活化的具体机制仍不明确。在本研究中，我们发现哮喘患者和小鼠模型中嗜酸性粒细胞的溶酶体酸度和组织蛋白酶L（cathepsin L）活性均显著升高。在嗜酸性粒细胞中基因敲除或药物抑制组织蛋白酶L可减轻体内过敏性气道炎症，并在体外抑制嗜酸性粒细胞的活化。嗜酸性粒细胞中的组织蛋白酶L通过上调并与其互作精氨酸酶1（arginase 1, ARG1），增强ARG1活性并改变嗜酸性粒细胞活化过程中的精氨酸代谢，从而促进2型免疫反应。这一代谢转变导致鸟氨酸生成增加，从而加剧炎症过程。此外，嗜酸性粒细胞中的溶酶体酸度与组织蛋白酶L活性还与哮喘患者的疾病严重程度相关。我们的研究结果揭示，溶酶体酸度和组织蛋白酶L通过调控精氨酸代谢促进嗜酸性粒细胞活化，从而加剧过敏性气道炎症。
Lysosomal acidity and cathepsin L activate eosinophils via ARG1-mediated arginine metabolism in allergic airway inflammation
Han Y, Li N, Zhao Y, Jin Z, Lv B, Shen D, Chen X, Weng Q, Zhang M, Chen K, Dong L, Liu Z, Lou J, Gao S, Wang Y, Hua W, Yan F, Ying S, Wu Y, Chen Z, Li W.
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.
嗜酸性粒细胞是哮喘发病机制中最重要的免疫细胞，因此亟需寻找减轻其作用的策略。尽管已有研究提示溶酶体在嗜酸性粒细胞功能中具有重要作用，但其在哮喘过程中对嗜酸性粒细胞活化的具体机制仍不明确。在本研究中，我们发现哮喘患者和小鼠模型中嗜酸性粒细胞的溶酶体酸度和组织蛋白酶L（cathepsin L）活性均显著升高。在嗜酸性粒细胞中基因敲除或药物抑制组织蛋白酶L可减轻体内过敏性气道炎症，并在体外抑制嗜酸性粒细胞的活化。嗜酸性粒细胞中的组织蛋白酶L通过上调并与其互作精氨酸酶1（arginase 1, ARG1），增强ARG1活性并改变嗜酸性粒细胞活化过程中的精氨酸代谢，从而促进2型免疫反应。这一代谢转变导致鸟氨酸生成增加，从而加剧炎症过程。此外，嗜酸性粒细胞中的溶酶体酸度与组织蛋白酶L活性还与哮喘患者的疾病严重程度相关。我们的研究结果揭示，溶酶体酸度和组织蛋白酶L通过调控精氨酸代谢促进嗜酸性粒细胞活化，从而加剧过敏性气道炎症。
（中日友好医院呼吸与危重症医学科 沈焜路 摘译 林江涛 审校）
（Nat Commun. 2025 Nov 25; DOI: 10.1038/s41467-025-65400-z ）
（Nat Commun. 2025 Nov 25; DOI: 10.1038/s41467-025-65400-z ）
Lysosomal acidity and cathepsin L activate eosinophils via ARG1-mediated arginine metabolism in allergic airway inflammation
Han Y, Li N, Zhao Y, Jin Z, Lv B, Shen D, Chen X, Weng Q, Zhang M, Chen K, Dong L, Liu Z, Lou J, Gao S, Wang Y, Hua W, Yan F, Ying S, Wu Y, Chen Z, Li W.
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.
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