Where the Aryl Hydrocarbon Receptor Meets the microRNAs: Literature Review of the Last 10 Years

Abstract

The aryl hydrocarbon receptor (AhR) is an environmentally responsive ligand-activated transcription factor, identified in the ‘70s for its toxic responses to halogenated polycyclic aromatic hydrocarbons, such as dioxin. Recently, AhR has been recognized as engaged in multiple physiological processes in health and diseases, particularly in the immune system, inflammatory response, tumorigenesis, and cellular differentiation by epigenetic mechanisms involving miRNAs. However, there is still scarce information about AhR-dependent miRNA regulation and miRNA-mediated epigenetic control in pathologies and therapies. In this review, we explore the mutual regulation of AhR and miRNA over the last decade of studies since many miRNAs have dioxin response elements (DRE) in their 3’ UTR, as well as AhR might contain binding sites of miRNAs. TCDD is the most used ligand to investigate the impact of AhR activation, and the immune system is one of the most sensitive of its targets. An association between TCDD-activated AhR and epigenetic mechanisms like post-transcriptional regulation by miRNAs, DNA methylation, or histone modification has already been confirmed. Besides, several studies have shown that AhR-induced miR-212/132 cluster suppresses cancers, attenuates autoimmune diseases, and has an anti-inflammatory role in different immune responses by regulating cytokine levels and immune cells. Together the ever-expanding new AhR roles and the miRNA therapeutics are a prominent segment among biopharmaceuticals. Additionally, AhR-activated miRNAs can serve as valuable biomarkers of diseases, notably cancer progression or suppression and chemical exposure. Once AhR-dependent gene expression may hinge on the ligand, cell type, and context singularity, the reviewed outcomes might help contextualize state of the art and support new trends and emerging opportunities in the field.

Interactions between Tryptophan Metabolism, the Gut Microbiome and the Immune System as Potential Drivers of Non-Alcoholic Fatty Liver Disease (NAFLD) and Metabolic Diseases

“…Metabolites such as tryptamine (TRP), 3-methylindole (3MI), indole-3-acetaldehyde, IA, indole-3-aldehyde, indole acrylic acid, kynurenine, KA, XA and 5-hydroxyindoleacetic acid (5-HIAA) are ligands for AhR [56,57]. AhR is expressed throughout the body, but highest levels are found in the intestine, lung and skin, and it has been shown to regulate the immune system through several mechanisms [58] such as regulation of the differentiation of Th17 and Treg cells (see Figure 4) [59,60]. Bridging microbial metabolites and inflammation are several human receptors affecting the immune system such the aryl hydrocarbon receptor (AhR) and the pregnane X receptor (PXR) [55].…”

MicroRNAs: Potential mediators between particulate matter 2.5 and Th17/Treg immune disorder in primary membranous nephropathy

“…PM2.5 may also promote PLA2R1 exposure by activating AhR on podocytes ( Li et al, 2018b ). And AhR is believed to be involved in various responses such as immune inflammation by altering the epigenetic mechanism of miRNAs ( Disner et al, 2021 ). However, there are few studies on this process in PMN.…”

TnP Peptide Suppresses Experimental Autoimmune Encephalomyelitis (EAE) in a Preclinical Mouse Model

“…Furthermore, exploring the possible multiple molecular gene-targets of miR-21, miR-122, miR-731, and miR-26 overexpressed by Tn P we concluded that, through this miRNA pathway, Tn P can regulate many genes in one pathway or even multiple cross-pathways, generating a tremendous impact on a complex regulatory network and, consequently, on the magnitude of neurogenesis and inflammation ( 19 , 20 ).…”