Esrrg Inhibition Protects against Fine Particulate Matter-induced Asthma Aggravation by Reducing Pde3b.

Abstract

Particulate matter ⩽2.5 μm in aerodynamic diameter (PM_2.5), exposure is closely linked to the exacerbation of asthma. Esrrg (estrogen-related receptor-γ), an orphan nuclear receptor, exerts a crucial role as a transcription factor in various metabolic diseases. Nevertheless, the impacts of Esrrg on PM_2.5-triggered asthma aggravation have not been investigated. Herein, ovalbumin (OVA)-induced asthmatic mice were exposed to PM_2.5 to establish a mouse model of asthma aggravation by PM_2.5. In view of mRNA sequencing, Esrrg was the only member of the nuclear receptor superfamily in the upregulated differentially expressed genes in OVA compared with naive groups as well as OVA + PM_2.5 compared with OVA groups (|log₂ (fold change)| > 1 and P < 0.05). In vivo, adenoassociated virus (AAV) carrying Esrrg shRNA (AAV-shEsrrg) was applied to silence Esrrg. In addition, Esrrg activity was suppressed pharmacologically with an inverse agonist, GSK5182. AAV-shEsrrg or GSK5182 ameliorated airway inflammation in the PM_2.5-aggravated asthmatic mice. In vitro, isolated mouse primary tracheobronchial epithelial cells from mice were identified by detecting cytokeratin 7-positive cells. The treatment of adenovirus vector with shEsrrg or GSK5182 mitigated the cell damage induced by PM_2.5. Notably, Pde3b (phosphodiesterase 3B) expression was decreased by Esrrg inhibition in vivo and in vitro. Dual luciferase reporter and chromatin immunoprecipitation PCR assays showed the binding of Esrrg to the Pde3b promoter. Taken together, these results revealed that Esrrg inhibition alleviated airway inflammation in the PM_2.5-deteriorated asthmatic mouse model and prevented PM_2.5-driven mouse primary tracheobronchial epithelial cell injury through binding to the Pde3b promoter, which might contribute to further study of therapies for PM_2.5-aggravated asthma.