Zhang Zhihua, Cai Tao, Zhang Xin, Li Xingbin, Wang Xin
Hebei Chest Hospital, Department of Science and Education, Shijiazhuang, Hebei, China.
Hebei Provincial Key Laboratory of Lung Disease, Shijiazhuang, Hebei, China.
Am J Respir Cell Mol Biol. 2025 Mar 28. doi: 10.1165/rcmb.2024-0461OC.
PM2.5 exposure is closely linked to the exacerbation of asthma. Estrogen related receptor gamma (Esrrg), an orphan nuclear receptor, exerts a crucial role as a transcription factor in various metabolic diseases. Nevertheless, the impacts of Esrrg on PM2.5-triggered asthma aggravation have not been investigated. Herein, ovalbumin (OVA)-induced asthmatic mice were exposed to PM2.5 to establish a mouse model of asthma aggravation by PM2.5. In view of mRNA sequencing, was the only member of nuclear receptor superfamily in the up-regulated differentially expressed genes in OVA compared with Naive groups as well as OVA+PM2.5 compared with OVA groups (|log (fold change)|>1 and p<0.05). , adeno-associated virus carrying shRNA (AAV-shEsrrg) was applied to silencing Esrrg. In addition, Esrrg activity was suppressed pharmacologically with an inverse agonist GSK5182. Either AAV-shEsrrg or GSK5182 ameliorated airway inflammation in the PM2.5-aggravated asthmatic mice. , isolated mouse primary tracheobronchial epithelial cells (MTEC) 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 PM2.5. Notably, phosphodiesterase 3B (Pde3b) expression was declined by Esrrg inhibition and . Dual luciferase reporter and ChIP-PCR assays showed the binding of Esrrg to the Pde3b promoter. Taken together, these results revealed that Esrrg inhibition alleviated airway inflammation in the PM2.5-deteriorated asthmatic mouse model and prevented PM2.5-driven MTEC injury through binding to the promoter, which might contribute to further study the therapy of PM2.5-aggravated asthma.
暴露于细颗粒物2.5（PM2.5）与哮喘加重密切相关。雌激素相关受体γ（Esrrg）作为一种孤儿核受体，在各种代谢性疾病中作为转录因子发挥着关键作用。然而，Esrrg对PM2.5引发的哮喘加重的影响尚未得到研究。在此，用卵清蛋白（OVA）诱导哮喘小鼠暴露于PM2.5，以建立PM2.5加重哮喘的小鼠模型。基于mRNA测序，与未致敏组相比，OVA组以及与OVA组相比的OVA + PM2.5组中，上调的差异表达基因中，Esrrg是核受体超家族的唯一成员（|log（倍数变化）|>1且p<0.05）。应用携带Esrrg短发夹RNA（AAV-shEsrrg）的腺相关病毒来沉默Esrrg。此外，用反向激动剂GSK5182在药理学上抑制Esrrg活性。AAV-shEsrrg或GSK5182均可改善PM2.5加重的哮喘小鼠的气道炎症。从小鼠中分离出的小鼠原代气管支气管上皮细胞（MTEC）通过检测细胞角蛋白7阳性细胞进行鉴定。用shEsrrg或GSK5182处理腺病毒载体可减轻PM2.5诱导的细胞损伤。值得注意的是，Esrrg抑制可降低磷酸二酯酶3B（Pde3b）的表达。双荧光素酶报告基因和染色质免疫沉淀PCR分析表明Esrrg与Pde3b启动子结合。综上所述，这些结果表明，Esrrg抑制可减轻PM2.5恶化的哮喘小鼠模型中的气道炎症，并通过与Pde3b启动子结合预防PM2.5驱动的MTEC损伤，这可能有助于进一步研究PM2.5加重哮喘的治疗方法。
