Dysregulation of Bmal1 in airway epithelial cells caused a decrease in response to glucocorticoid in HDM-induced asthma

Object: Corticosteroid therapy is the mainstay treatment in the clinical management of asthma. However, there are still a considerable number of asthmatics that have poor sensitivity to glucocorticoids. Recently studies linked steroid insensitivity in asthma to defects in glucocorticoid receptor (GR) expression and activity. The circadian rhythm is a biological rhythm with a periodicity of approximately 24 hours and is observed in the behavior and physiology of virtually all living organisms. Dysregulation of clock activity not only enhance the severity of allergic reactions but also increase susceptibility to allergic disease. So we established both in vitro and in vivo asthma model with house dust mite (HDM) treatment and explored whether Bmal1 could be be involved in regulating sensitivity to glucocorticoids of airway epithelial cell to promote the occurrence and development of refractory asthma. <bold>Methods:</bold> Bmal1 knockout (Bmal1-KO) mice and human bronchial epithelial cell line (HBE135) were used to build the asthma model induced by HDM treated with or without dexamethasone. <bold>Results:</bold> We found that treatment with HDM caused a significantly decrease in expression of Bmal1 and GR. In addition, gene knockdown of Bmal1 could further trigger a down-regulation of GR and reduce the anti-inflammatory effect of dexamethasone. <bold>Conclusion:</bold> 1. Clock gene Bmal1 of airway epithelial cells malfunctioned in asthmatics and HDM-induced model. 2. Down-regulation of Bmal1 of airway epithelial cells caused defects in GR leading to decreased reactivity to dexamethasone.