Disruption of the Clock Component BMAL1 in HDM-induced Asthma Causes GC Resistance in Airway Epithelial Cells by Regulating GR Phosphorylation through the DUSP4-p38MAPK Pathway

TL;DR

Disrupting the BMAL1 gene in asthma worsens inflammation and causes resistance to glucocorticoid treatment by altering GR phosphorylation through the DUSP4-p38MAPK pathway.

Contribution

The study reveals a novel mechanism linking circadian disruption to GC resistance in asthma via the BMAL1-DUSP4-p38MAPK-GR pathway.

Findings

BMAL1 disruption increases airway inflammation and GC resistance by activating NF-κB and AP-1 pathways.

BMAL1 deletion reduces GR phosphorylation, impairing GC efficacy in asthma.

Inhibiting DUSP4 restores GR activation and improves GC responsiveness in HDM-induced asthma.

Abstract

Circadian rhythm disruption has been increasingly implicated in asthma and glucocorticoid (GC) resistance. In this study, we discovered that disruption of the brain and muscle ARNT-like 1 (BMAL1), a significant activator of the circadian clock transcription, not only exacerbated allergic inflammation but also induced GC resistance. The absence of BMAL1 intensified airway inflammation by activating the NF-κB and AP-1 pathways and also impaired the anti-inflammatory effect of GC. Our findings indicated that the deletion of BMAL1 reduced the phosphorylation level of the GC receptor (GR-Ser211), which has a direct effect on the efficacy of GC and serves as a key indicator of GR activation. Additionally, BMAL1 has a negative regulatory effect on the phosphatase dual specificity protein phosphatase 4 (DUSP4) of p38 mitogen-activated protein kinase (p38MAPK), which plays a crucial role in the phosphorylation of GR. Consequently, our findings suggest that the absence of BMAL1 results in the resistance of airway epithelial cells to GC due to the inhibition of GR phosphorylation via the DUSP4-p38MAPK axis in HDM-induced asthma. We demonstrated that the inhibition of DUSP4 restored GR activation and improved GC responsiveness, highlighting a potential therapeutic strategy for GC resistance driven by circadian disruption. Regulating the sleep disorder and circadian rhythm of patients with asthma could become a potential treatment to increase GC sensitivity.

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