Mucin 1 deficiency mediates corticosteroid insensitivity in asthma

Abstract Background The loss of corticosteroid efficacy is an important issue in severe asthma management and may lead to poor asthma control and deterioration of airflow. Recent data indicate that Mucin 1 ( MUC 1) membrane mucin can mediate corticosteroid efficacy in chronic rhinosinusitis, but the role of MUC 1 in uncontrolled severe asthma is unknown. The objective was to analyze the previously unexplored role of MUC 1 on corticosteroid efficacy in asthma. Methods Mucin 1 expression was evaluated by real‐time PCR in human bronchial epithelial cells ( HBEC ) and blood neutrophils from uncontrolled severe asthma (n = 27), controlled mild asthma (n = 16), and healthy subjects (n = 13). IL ‐8, MMP 9, and GM ‐ CSF were measured by ELISA in HBEC and neutrophils. An asthma model of ovalbumin ( OVA ) was used in MUC 1 KO and WT C57 BL /6 mice according to ARRIVE guidelines. Results Mucin 1‐ CT expression was downregulated in bronchial epithelial cells and peripheral blood neutrophils from severe asthma patients compared with mild asthma and healthy subjects ( P < 0.05). Daily dose of inhaled corticosteroids ( ICS ) inversely correlated with MUC 1 expression in neutrophils from mild and severe asthma (ρ = −0.71; P < 0.0001). Dexamethasone showed lower anti‐inflammatory effects in severe asthma peripheral blood neutrophils and HBEC s stimulated with lipopolysaccharide ( LPS ) than in cells from mild asthma. Glucocorticoid receptor ( GR )‐α phosphorylated at serine 226 was increased in cells from severe asthma, and the MUC 1‐ CT / GR α complex was downregulated in severe asthma cells. OVA asthma model in MUC 1 KO mice was resistant to the anti‐inflammatory effects of dexamethasone. Conclusion Mucin 1‐ CT modulates corticosteroid efficacy in vitro and in vivo asthma models.