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

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, <i>Esrrg</i> 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 <i>P</i> < 0.05). <i>In vivo</i>, adenoassociated virus (AAV) carrying <i>Esrrg</i> 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. <i>In vitro</i>, 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 <i>in vivo</i> and <i>in vitro</i>. Dual luciferase reporter and chromatin immunoprecipitation PCR assays showed the binding of Esrrg to the <i>Pde3b</i> 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 <i>Pde3b</i> promoter, which might contribute to further study of therapies for PM_2.5-aggravated asthma.