Hu Xinyue, Deng Shuanglinzi, Luo Lisha, Jiang Yuanyuan, Ge Huan, Yin Feifei, Zhang Yingyu, Zhang Daimo, Li Xiaozhao, Feng Juntao
Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, China.
Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China.
Front Med (Lausanne). 2021 Aug 24;8:686493. doi: 10.3389/fmed.2021.686493. eCollection 2021.
GLCCI1 plays a significant role in modulating glucocorticoid (GC) sensitivity in asthma. This project determines the underlying mechanism that GLCCI1 deficiency attenuates GC sensitivity in dexamethasone (Dex)-treated Ovalbumin (OVA)-induced asthma mice and epithelial cells through upregulating binding of IRF1:GRIP1 and IRF3:GRIP1. Dexamethasone treatment led to less reduced inflammation, airway hyperresponsiveness, and activation of the components responsible for GC activity, as determined by decreased GR and glucocorticoid receptor interacting protein 1 (GRIP1) expression but augmented IRF1 and IRF3 expression in GLCCI1 asthmatic mice compared with wild type asthmatic mice. Moreover, the recruitment of GRIP1 to GR was downregulated, while the individual recruitment of GRIP1 to IRF1 and IRF3 was upregulated in GLCCI1 Dex-treated asthmatic mice compared to wild type Dex-treated asthmatic mice. We also found that GLCCI1 knockdown reduced GR and GRIP1 expression but increased IRF1 and IRF3 expression in Beas2B and A549 cells. Additionally, GLCCI1 silencing increased the interactions between GRIP1 with IRF1 and GRIP1 with IRF3, but decreased the recruitment of GRIP1 to GR. These studies support a critical but previously unrecognized effect of GLCCI1 expression on epithelial cells in asthma GC responses by which GLCCI1 deficiency reduces the GR and GRIP1 interaction but competitively enhances the recruitment of GRIP1 to IRF1 and IRF3.
GLCCI1在调节哮喘中糖皮质激素（GC）敏感性方面发挥着重要作用。本项目确定了GLCCI1缺陷通过上调IRF1:GRIP1和IRF3:GRIP1的结合，减弱地塞米松（Dex）处理的卵清蛋白（OVA）诱导的哮喘小鼠和上皮细胞中GC敏感性的潜在机制。地塞米松治疗导致炎症减轻、气道高反应性降低以及负责GC活性的成分的激活减少，这通过与野生型哮喘小鼠相比，GLCCI1哮喘小鼠中糖皮质激素受体（GR）和糖皮质激素受体相互作用蛋白1（GRIP1）表达降低，但IRF1和IRF3表达增加来确定。此外，与野生型地塞米松处理的哮喘小鼠相比，GLCCI1地塞米松处理的哮喘小鼠中GRIP1与GR的募集下调，而GRIP1与IRF1和IRF3的单独募集上调。我们还发现，在Beas2B和A549细胞中，GLCCI1基因敲低降低了GR和GRIP1的表达，但增加了IRF1和IRF3的表达。此外，GLCCI1沉默增加了GRIP1与IRF1以及GRIP1与IRF3之间的相互作用，但减少了GRIP1与GR的募集。这些研究支持了GLCCI1表达对哮喘GC反应中上皮细胞的关键但先前未被认识的作用，即GLCCI1缺陷减少了GR和GRIP1的相互作用，但竞争性地增强了GRIP1与IRF1和IRF3的募集。
