CTSS contributes to airway neutrophilic inflammation in mixed granulocytic asthma

• Published in: Respiratory research 2024-12, Vol.25 (1), p.441-11, Article 441
• Main Authors: Tang, Haixiong, Li, Zhongli, Yang, Changyun, Fu, Lin, Ji, Xiaolong, Chen, Zemin, Gan, Sudan, Zhang, Hailing, Zhang, PingAn, Li, Shiyue, Zhang, Wenjun, Chen, Xin, Yao, Lihong, Li, Jing
• Format: Article
• Language: English
• Subjects: Adult; Akt; Animals; Asthma; Asthma - drug therapy; Asthma - immunology; Asthma - metabolism; Asthma - pathology; Cathepsins; Complications and side effects; CTSS; Development and progression; Disease Models, Animal; Female; Granulocytes - drug effects; Granulocytes - immunology; Granulocytes - metabolism; Health aspects; Humans; Inflammation; Male; Mice; Mice, Inbred BALB C; Middle Aged; Mixed granulocytic asthma; Neutrophils; Neutrophils - drug effects; Neutrophils - immunology; Neutrophils - metabolism; Risk factors; Sputum - metabolism; Young Adult
• ISSN: 1465-993X; 1465-9921; 1465-993X
• DOI: 10.1186/s12931-024-03077-6

Mixed granulocytic asthma (MGA) is usually associated with poor response to corticosteroid therapy and a high risk of severe asthma. Cathepsin S (CTSS) has been found to play an important role in various inflammatory diseases. This study was aimed to investigate the role of CTSS in MGA. Induced sputum was obtained from healthy subjects and asthma patients. Two murine models of MGA were established using either TDI (toluene diisocyanate) alone or OVA emulsified in CFA. LY3000328, a specific antagonist of CTSS, was therapeutically given to BALB/c mice after airway challenge with TDI or OVA. The effects of recombinant CTSS was tested in vivo, and Akt inhibition was used to explore a possible mechanism for CTSS-induced airway inflammation. MGA patients have a significant higher sputum CTSS level than the health and subjects with other inflammatory phenotypes, which was positively correlated with sputum level of soluble E-cadherin (sE-cadherin), sputum neutrophils, FeNO, FEF25-75% and glucocorticoid dosage. Allergen exposure markedly increased CTSS level and pharmacological antagonism of CTSS with LY3000328 decreased airway hyperresponsiveness, airway neutrophil accumulation, as well as the release of IL-17 and sE-cadherin in murine models of MGA, yet had no effects on eosinophilic inflammation nor type 2 inflammatory cytokines (IL-4 and IL-5). In addition, intratracheal instillation of recombinant CTSS leads to neutrophil recruitment and overproduction of sE-cadherin in the lung tissues, which could be attenuated by inhibition of Akt signaling. Our data suggested that CTSS contributes to airway neutrophilic inflammation in MGA through an Akt-dependent pathway.