Epithelium‐derived cystatin SN inhibits house dust mite protease activity in allergic asthma

• Published in: Allergy (Copenhagen) Vol. 78; no. 6; pp. 1507 - 1523
• Main Authors: Yao, Lei, Yuan, Xijing, Fu, Heng, Guo, Qinxing, Wu, Yunhui, Xuan, Shurui, Kermani, Nazanin Zounemat, Adcock, Ian M., Zeng, Xiaoning, Liu, Yi, Xie, Min, Yao, Xin
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01.06.2023
• Subjects: allergenicity; Allergens; Animals; Antigens, Dermatophagoides; Asthma; Asthma - etiology; biomarkers; blood serum; CST1; CST1 protein; Cystatins; Cysteine; Cysteine Proteases; Cysteine proteinase; cysteine proteinases; Dermatophagoides pteronyssinus; Dust; dust mites; enzyme activity; epithelial barrier function; Epithelium; HDM; Humans; Immunoglobulin E; inflammation; lung function; Mice; Peptide Hydrolases; Proteins; Pyroglyphidae; Respiratory function; Salivary Cystatins; Sputum; HDM; CST1; asthma; epithelial barrier function
• ISSN: 0105-4538; 1398-9995; 1398-9995
• DOI: 10.1111/all.15739

Background Allergen source‐derived proteases are a critical factor in the formation and development of asthma. The cysteine protease activity of house dust mite (HDM) disrupts the epithelial barrier function. The expression of cystatin SN (CST1) is elevated in asthma epithelium. CST1 inhibits the cysteine protease activity. We aimed to elucidate the role of epithelium‐derived CST1 in the development of asthma caused by HDM. Methods CST1 protein levels in sputum supernatants and serum of patients with asthma and healthy volunteers were measured by ELISA. The ability of CST1 protein to suppress HDM‐induced bronchial epithelial barrier function was examined in vitro. The effects of exogenous CST1 protein on abrogating HDM‐induced epithelial barrier function and inflammation were examined in mice in vivo. Results CST1 protein levels were higher in sputum supernatants (142.4 ± 8.95 vs 38.87 ± 6.85 ng/mL, P < 0.0001) and serum (1129 ± 73.82 vs 703.1 ± 57.02 pg/mL, P = 0.0035) in patients with asthma than in healthy subjects. The levels were significantly higher in patients with not well‐ and very poorly controlled asthma than those with well‐controlled asthma. Sputum and serum CST1 protein levels were negatively correlated with lung function in asthma. CST1 protein levels were significantly lower in the serum of HDM‐specific IgE (sIgE)‐positive asthmatics than in sIgE‐negative asthmatics. The HDM‐induced epithelial barrier function disruption was suppressed by recombinant human CST1 protein (rhCST1) in vitro and in vivo. Conclusion Our data indicated that human CST1 protein suppresses asthma symptoms by protecting the asthmatic bronchial epithelial barrier through inhibiting allergenic protease activity. CST1 protein may serve as a potential biomarker for asthma control. Sputum and serum CST1 protein levels are elevated in asthma and negatively correlated with lung function. IL‐13 induces upregulation of CST1 in 16HBE, whereas rhCST1 protein inhibits protease activity of HDM. HDM‐induced epithelial barrier function disruption is suppressed by rhCST1 protein in vitro. Intranasal administration of rhCST1 reduces AHR, inflammation, and epithelial barrier function in mice.Abbreviations: ACT, asthma control test; AHR, airway hyperresponsiveness; CST1, cystatin SN; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; HDM, house dust mite; IL, interleukin; rhCST1, recombinant human CST1; SCGB1A1, secretoglobin family 1A member 1; sIgE, specific immunoglobulin E; 16HBE, human bronchial epithelial cell line