Crosstalk between Aryl Hydrocarbon Receptor and Glucocorticoid Receptor in Human Retinal Pigment Epithelial Cells

Abstract

The aryl hydrocarbon receptor (AHR) is known to mediate the cellular reaction involved in processing environmental contaminants and, ultimately, preventing accumulation of unfavorable extra lipids and proteins. Glucocorticoid receptor (GR) mediates the expression of genes associated with anti-inflammatory properties. Because AHR and GR are closely related in lipid metabolic dysregulation and inflammation, we speculate that AHR and GR may play a crucial role in AMD pathogenesis and focus on their crosstalk in human retinal pigment epithelial cells (ARPE-19). However, how AHR and GR regulate each other's signaling pathways is still poorly understood. In this research, we demonstrate that GR attenuates AHR-mediated gene expression by inhibition of nuclear translocation of AHR mediated by TCDD. Chromatin immunoprecipitation analysis demonstrated that GR repress AHR recruitment and chromatin accessibility response to TCDD + Dex treatment leading to repression of AHR target genes. In contrast, AHR facilitates GR-mediated expression in ARPE-19. AHR increases GR recruitment on GRE of GR target genes. Coimmunoprecipitation assay revealed that AHR is associated with GR in ARPE-19 cells and the interaction is enhanced by the addition of TCDD and Dex. Taken together, these studies provide a molecular mechanism of crosstalk between AHR and GR in target gene expression in ARPE-19 cells.

Dexamethasone for the Treatment of Coronavirus Disease (COVID-19): a Review

“…The atomic details of the interaction between the receptor-binding domain (RBD) and the peptidase domain of human ACE-2 protein (Fig. 1 ) clarify the significance of residual differences that enable effective cross-species infection and in addition human-to-human transmission [ 14 ]. Therefore, the soluble SARS-CoV-2 RBD is of probable use as an immunogen which is capable of neutralizing antibodies against SARS-CoV-2.…”

“…Therefore, the soluble SARS-CoV-2 RBD is of probable use as an immunogen which is capable of neutralizing antibodies against SARS-CoV-2. This is considered a significant target site for developing vaccines and immunotherapeutic agents [ 14 , 15 ]. Recently, Hoffmann et al [ 16 ] documented the same fact that SARS-CoV-2 uses the SARS-CoV receptor ACE-2 for entrance and the serine protease TMPRSS2 for S protein priming.…”

The Aryl Hydrocarbon Receptor: A Mediator and Potential Therapeutic Target for Ocular and Non-Ocular Neurodegenerative Diseases

“…Physiologically and functionally, these non-classical pathways may converge leading to regulation of inflammation [53,54]. Interestingly, the glucocorticoid receptor pathway has been shown in a human retinal pigment epithelial cell line, to interact with the AHR pathway and modulate its transcriptional activity [55]. The AHR is also known to interact with transcriptional and epigenetic regulators to exert genome-wide effects [56,57], regulating histone acetylation and methylation, through species-specific and cell type-specific mechanisms [56][57][58].…”

The Aryl Hydrocarbon Receptor as a Modulator of Anti-viral Immunity

“…Regarding the non-canonical genomic regulation, it has been reported that AHR can heterodimerize with other nuclear proteins, including transcription factors, to modulate their activity by transactivation/transrepression or protein-protein interactions. In this context, AHR has been shown to cross-talk with the nuclear factor kappa light chain enhancer of activated B cells (NFκB), activator protein-1 (AP-1), estrogen receptor (ER) and glucocorticoid receptor (GR), Krüppel-like Factor 4 and 6 (KLF4, KLF6), signal transducers and activators of transcription (STAT) proteins and members of the CCAAT-enhancer-binding proteins (C/EBP) family (2,20,21,(30)(31)(32)(33)(34) (Figure 1B).…”