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

Abstract

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.

Proteomic signatures of eosinophilic and neutrophilic asthma from serum and sputum

“…Cystatin SN (CYTN) encoded by CST1 is a cysteine proteinase inhibitor that has been found to be higher in sputum supernatants and serum in poorly-controlled asthmatics compared to well-controlled asthma 31 and is also upregulated in allergic rhinitis. 32 Cystatin SN prevents the disruption of the airway epithelial barrier by allergen proteases.…”

“… 32 Cystatin SN prevents the disruption of the airway epithelial barrier by allergen proteases. 31 TARC/CCL17 and IgE levels are upregulated in elderly patients with asthma (and allergic asthma). 33 TARC/CCL17 is a chemoattractant of Th2 cells, 34 which explains its association with eosinophilic asthma but not the link with ageing which needs further research.…”

How does allergen immunotherapy‐induced tolerance improve the airway epithelial barrier function: A mechanistical‐driven hypothesis

“…For instance, a cross‐over double‐blind, randomized controlled trial involving six mild atopic steroid‐naïve asthmatic subjects demonstrated that three doses of an inhaled cationic airway lining modulator had well‐tolerated effects, resulting in attenuation of allergen‐induced sputum eosinophils and reduction of IL‐5, MCP‐1, and eotaxin levels 10 . Moreover, a separate study identified the human CST1 protein as an inhibitor of allergenic protease activity, effectively safeguarding the bronchial epithelial barrier in individuals with asthma, and suggesting CST1 as a promising biomarker for asthma control 11 …”

Resolving the etiology and treatments of allergic diseases

“…Yin and colleagues 9 noticed that aberrant lipid metabolism in sebaceous glands was correlated with skin inflammation and barrier dysfunction, and contributed to the pathogenesis of AD. Another group indicated that human CST1 protein suppressed asthma symptoms by protecting the asthmatic bronchial epithelial barrier through inhibiting allergenic protease activity, indicating CST1 as a potential biomarker for asthma control 10 . The “allergic march” from early AD to asthma and/or AR later in life as well as the extensive comorbidity of allergic disorders has frequently been observed in real life.…”

“…Another group indicated that human CST1 protein suppressed asthma symptoms by protecting the asthmatic bronchial epithelial barrier through inhibiting allergenic protease activity, indicating CST1 as a potential biomarker for asthma control. 10 The "allergic march" from early AD to asthma and/or AR later in life as well as the extensive comorbidity of allergic disorders has frequently been observed in real life. Data from a real-life study investigating the effectiveness of dupilumab for AD patients of different ages suggest that pediatric patients may respond to dupilumab to a significantly greater level than adults.…”