BMAL1/p53 mediating bronchial epithelial cell autophagy contributes to PM2.5-aggravated asthma

Abstract

Background Fine particulate matter (PM2.5) is associated with increased incidence and severity of asthma. PM2.5 exposure disrupts airway epithelial cells, which elicits and sustains PM2.5-induced airway inflammation and remodeling. However, the mechanisms underlying development and exacerbation of PM2.5-induced asthma were still poorly understood. The aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1) is a major circadian clock transcriptional activator that is also extensively expressed in peripheral tissues and plays a crucial role in organ and tissue metabolism. Results In this study, we found PM2.5 aggravated airway remodeling in mouse chronic asthma, and exacerbated asthma manifestation in mouse acute asthma. Next, low BMAL1 expression was found to be crucial for airway remodeling in PM2.5-challenged asthmatic mice. Subsequently, we confirmed that BMAL1 could bind and promote ubiquitination of p53, which can regulate p53 degradation and block its increase under normal conditions. However, PM2.5-induced BMAL1 inhibition resulted in up-regulation of p53 protein in bronchial epithelial cells, then increased-p53 promoted autophagy. Autophagy in bronchial epithelial cells mediated collagen-I synthesis as well as airway remodeling in asthma. Conclusions Taken together, our results suggest that BMAL1/p53-mediated bronchial epithelial cell autophagy contributes to PM2.5-aggravated asthma. This study highlights the functional importance of BMAL1-dependent p53 regulation during asthma, and provides a novel mechanistic insight into the therapeutic mechanisms of BMAL1. Graphic abstract

Knockdown of KIF23 alleviates the progression of asthma by inhibiting pyroptosis

“…Fortilin, an anti-p53 molecule, inhibits p53 to prevent cardiomyocyte apoptosis, protecting the heart from heart failure 34. Furthermore, in bronchial epithelial cells, BMAL1/p53 mediates autophagy to exacerbate asthma induced by PM2.5 35. In addition, the p53 pathway can also mediate pyroptosis to affect the development of several diseases.…”

“… 34 Furthermore, in bronchial epithelial cells, BMAL1/p53 mediates autophagy to exacerbate asthma induced by PM2.5. 35 In addition, the p53 pathway can also mediate pyroptosis to affect the development of several diseases. In clear renal cell carcinoma, silencing linc00023 significantly inhibits pyroptosis by regulating p53.…”