AUTHOR=Hu Xinyue , Deng Shuanglinzi , Luo Lisha , Jiang Yuanyuan , Ge Huan , Yin Feifei , Zhang Yingyu , Zhang Daimo , Li Xiaozhao , Feng Juntao 

TITLE=GLCCI1 Deficiency Induces Glucocorticoid Resistance via the Competitive Binding of IRF1:GRIP1 and IRF3:GRIP1 in Asthma

JOURNAL=Frontiers in Medicine

VOLUME=Volume 8 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2021.686493

DOI=10.3389/fmed.2021.686493

ISSN=2296-858X

ABSTRACT=GLCCI1 plays a significant role in modulating glucocorticoid sensitivity in asthma. This project determines the underlying mechanism that GLCCI1 deficiency attenuates glucocorticoid sensitivity in dexamethasone-treated Ovalbumin-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 glucocorticoid activity, as determined by decreased GR and 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-/- dexamethasone-treated asthmatic mice compared to wild type dexamethasone-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 glucocorticoid responses by which GLCCI1 deficiency reduces the GR and GRIP1 interaction but competitively enhances the recruitment of GRIP1 to IRF1 and IRF3.