Targeting SOCE attenuates IL-17-driven airway inflammation in cigarette smoking-induced COPD mice

Background: Store-operated calcium entry (SOCE) is implicated in airway inflammation and remodeling in asthma. Chronic cigarette smoking (CS) exposure augments SOCE level in pulmonary arterial smooth muscle, contributing to CS-induced pulmonary hypertension. However, the regulatory role of SOCE and the therapeutic potential of its inhibitors in CS-induced COPD airway inflammation remains unclear. Methods: C57BL/6 mice were exposed to 12-week nose-only CS with or without nebulized SOCE inhibitor GSK7975A. Lung function tests were performed, and bronchoalveolar lavage fluid (BALF) and lung tissues were collected post exposure. Total/differential cell counts, and inflammatory cytokines levels in BALF were measured. Transcriptome sequencing (RNA-Seq) of lung tissue was performed. Primary airway epithelial cells were stimulated with CS extract (CSE), followed by mRNA and soluble protein quantification. Results: Nebulization with GSK-7975A attenuates airflow limitation and emphysema severity, and reduces neutrophil counts, CXCL5, IL-1β and IL-17C levels in BALF of COPD mice induced by CS exposure. RNA-Seq analysis on lung tissues reveals enrichment of downregulated differential expressed genes (DEGs) in the IL−17 signaling pathway. In vitro, GSK-7975A treatment suppresses mRNA and soluble protein expression of TNF-α, IL-1β and IL17C in primary airway epithelial cells exposed to CSE. Conclusion: SOCE inhibition alleviates CS-induced airway inflammation in COPD mice, an effect that appears to be linked to the attenuation of IL-17 signaling pathway. Therefore, targeting SOCE might represent a promising therapeutic strategy for managing airway inflammation associated with CS exposure.