Transcriptional Regulation of gga-miR-451 by AhR:Arnt in Mycoplasma gallisepticum (HS Strain) Infection

Abstract

MicroRNAs (miRNAs) have been determined to be important regulators for pathogenic microorganism infection. However, it is largely unclear how miRNAs are triggered during pathogen infection. We previously reported that the up-regulation of gga-miR-451 negatively regulates the Mycoplasma gallisepticum (MG)-induced production of inflammatory cytokines via targeting tyrosine3-monooxygenase/tryptophan5-monooxygenase activation protein zeta (YWHAZ). The aim of this study was to investigate the mechanism regulating gga-miR-451 in MG infection in chickens. Analysis of gga-miR-451 precursor, pri-miR-451, and pre-miR-451 indicated that the regulation occurred transcriptionally. We also identified the transcriptional regulatory region of gga-miR-451 that contained consensus-binding motif for aryl hydrocarbon receptor (AhR) and aryl hydrocarbon receptor nuclear translocator (Arnt) complex, which is known as the transcription factor that regulates gene expression. Luciferase reporter assays combined with chromatin immunoprecipitation (ChIP) demonstrated that AhR:Arnt bound directly to the promoter elements of gga-miR-451, which were responsible for gga-miR-451 transcription in the context of MG infection. Furthermore, upregulation of AhR:Arnt significantly induced gga-miR-451 and inhibited YWHAZ expression, suggesting that AhR:Arnt may play an anti-inflammatory role in MG infection. This discovery suggests that induced gga-miR-451 expression is modulated by AhR:Arnt in response to MG infection.

Analysis of deep sequencing Exosome-microRNA expression profile from Chicken Type Ⅱ Pneumocytes derived reveals potential role of gga-miRNA-451 in inflammation

“…It is worth mentioning that gga-miR-451 regulates the MG-induced production of inflammatory cytokines via targeting YWHAZ (16). Moreover, our previous study also confirmed that AhR:Arnt bind to the gga-miR-451 promoter and facilitate gga-miR-451 transcription in DF-1 cells (17).…”

Aryl Hydrocarbon Receptor Role in Co-Ordinating SARS-CoV-2 Entry and Symptomatology: Linking Cytotoxicity Changes in COVID-19 and Cancers; Modulation by Racial Discrimination Stress

“…There is a growing appreciation of the role of the melatonergic pathway, including within mitochondria and the cytoplasm, in the regulation of mitochondrial function, which may be particularly important in immune cells [ 25 ]. The AhR can regulate the melatonergic pathway via a number of mechanisms, including 1) the induction of CYP1A1 and CYP1B1, with CYP1A1 increasing the metabolism of estrogen, whilst CYP1B1 leads to the ‘backward’ conversion of melatonin to its precursor, NAS, and thereby increasing the NAS/melatonin ratio [ 26 ]; and 2) AhR suppression of YWHAZ (14-3-3ζ/δ) [ 8 ], given that 14-3-3ζ/δ is necessary to stabilize the initial enzyme in the melatonergic pathway AANAT. As the autocrine effects of melatonin are necessary for immune cells to switch from an M1-like pro-inflammatory phenotype to an M2-like phenotype [ 27 ], AhR activation, via inhibition of the melatonergic pathway, would be expected to contribute to a prolongation of the ‘cytokine storm’.…”

“…Consequently, an increase in kynurenine production and activation of the AhR is associated with a decrease in serotonin and melatonin. AhR activation, via cytochrome P450 (CYP) 1B1, may also lower melatonin availability, as will the AhR suppression of YWHAZ (14-3-3ζ/δ) [ 8 ], which is required to stabilize the first enzyme in the melatonergic pathway, aralkylamine N-acetyltransferase (AANAT). It is proposed that AhR activation and associated suppression of pineal and immune cell melatonin, coupled to the AhR’s suppression of acetyl-coenzyme A (CoA) and specialized pro-resolving mediators (SPMs), are crucial in driving the heightened cytokines underpinning the ‘cytokine storm’ as well as suppressing the endogenous anti-viral response.…”

Tumour Microenvironment: Roles of the Aryl Hydrocarbon Receptor, O-GlcNAcylation, Acetyl-CoA and Melatonergic Pathway in Regulating Dynamic Metabolic Interactions across Cell Types—Tumour Microenvironment and Metabolism

“…Such trophic effects of NAS may arise from any of the cells forming the tumour microenvironment, including NK cells and CD8+ t cells. As 14-3-3ζ/δ (YWHAZ) is crucial for AANAT stabilisation, the AhR inhibition of14-3-3ζ/δ [ 19 ], including via microRNAs, allows the AhR to suppress both NAS and melatonin production. As the melatonergic pathway seems to be evident in the cytoplasm and mitochondria of all investigated cells, the AhR may therefore exert some of its effect in different cellular compartments via melatonergic pathway regulation.…”