Crosstalk between the AHR signaling pathway and circadian rhythm

Shimba, Shigeki; Watabe, Yuichi

doi:10.1016/j.bcp.2008.09.040

Cited by 55 publications

(37 citation statements)

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“…Mechanistically, Per1, Per2, Cry1, and Cry2 interfere with Clock-Bmal1 activity to repress transcription targets (10,35). Since Per2 protein is nonfunctional in these mPer2-M mice and bmal1 (arntl) gene expression is increased in response to ischemia in the absence of reperfusion in mPer2-M versus WT mice, this would suggest that the repressor activity normally effected by mPer2 is alleviated and so targets could be upregulated.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of myocardial injury in mice with functional deletion of the circadian rhythm gene mPer2

Virag¹,

Dries²,

Easton³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Section: Discussionmentioning

confidence: 99%

Attenuation of myocardial injury in mice with functional deletion of the circadian rhythm gene mPer2

Virag¹,

Dries²,

Easton³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…Previous independent studies on circadian clock support our findings on the regulatory role of Ahr on the miR-132/AChE module. The Ahr mRNA peaks in the liver during the day and reaches the lowest level in the early morning [31]. Keeping this in mind, miR-132 expression is high during day time [19], whereas AChE peaks during the sleeping time [32].…”

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confidence: 99%

MicroRNA‐132 suppresses autoimmune encephalomyelitis by inducing cholinergic anti‐inflammation: A new Ahr‐based exploration

Hanieh

Abdullah

2013

Eur J Immunol

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MicroRNAs (miRNAs) are a small group of RNAs that are emerging as a new avenue by which autoimmune diseases may be modulated. Accumulating evidence shows that miRNAs are involved in the pathogenesis of MS; however, the interaction of miRNAs with environmentally responsive transcription factors that play prominent roles in MS is unexplored. The activation of aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) alleviates inflammation in experimental autoimmune encephalomyelitis (EAE), the best available model of MS. Therefore, we predicted that TCDD could attenuate EAE by inducing miRNA(s) targeting inflammatory mediators. Here, we show that TCDD induces cholinergic anti-inflammation in EAE mice by upregulating acetylcholinesterasetargeting miR-132. The expression of miR-132 was downregulated in CD4 + cells and associated with EAE severity, while TCDD treatment attenuated EAE by inducing the miR-132/acetylcholinesterase module. Silencing miR-132 in vivo abolished TCDDinduced cholinergic anti-inflammation and aggravated EAE. Overexpression of miR-132 in encephalitogenic CD4 + cells decreased IL-17 and IFN-γ and suppressed T-cell proliferation. In conclusion, our findings identify a new miRNA-based mechanism through which miR-132 mediates TCDD-induced EAE attenuation, suggesting that miR-132 could be a promising therapeutic target for anti-inflammatory treatment of MS.Keywords: Ahr r Cholinergic anti-inflammation r EAE · MicroRNA r miR-132 r TCDD Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe aryl hydrocarbon receptor (Ahr) is a ligand-dependent transcription factor activated by a long list of exogenous ligands including 2,3,7, [1] and 3-methylcholanthrene [2]. Ahr has been shown to mediate the mechanisms that underlie environmental and immunotoxicity [3]. Therefore, Ahr represents a fascinating link between the environment and the immune system. Previously, we and others have Correspondence: Dr. Hanieh Hamza e-mail: hhanieh@kfu.edu.sa demonstrated that Ahr is implicated in the differentiation of Th17/Treg cells [4][5][6], development of autoimmunity [7], and secretion of proinflammatory cytokines [8,9]. Importantly, activation of Ahr has shown a therapeutic potential for autoimmune inflammation. For example, TCDD mitigates CNS inflammation in experimental autoimmune encephalomyelitis (EAE) [5], an established animal model of MS. However, the toxicity of TCDD prohibits its clinical application, and therefore, mechanistic explanation of TCDD-attenuated inflammation may open intriguing possibilities for applicable treatment of MS in human.The microRNAs (miRNAs) are small endogenous noncoding RNAs of ∼22 nt that post-transcriptionally regulate gene expression. These molecules are implicated in different aspects of C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Hanieh Hamza and Alzahrani AbdullahEur. J. Immunol. 2013Immunol. . 43: 2771Immunol. -2782 inflammation. For instance, miR-155, miR-146a, a...

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“…This well-described signaling pathway does not account for all effects of environmental toxicants, however. Crosstalk between AhR/ARNT and other nuclear receptors also contributes to toxicant-induced diseases (Puga et al 2009; Shimba and Watabe 2009). …”

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confidence: 99%

Aryl Hydrocarbon Receptor Deficiency Enhances Insulin Sensitivity and Reduces PPAR-α Pathway Activity in Mice

Wang

Krager

et al. 2011

Environ Health Perspect

116

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Background: Numerous man-made pollutants activate the aryl hydrocarbon receptor (AhR) and are risk factors for type 2 diabetes. AhR signaling also affects molecular clock genes to influence glucose metabolism.Objective: We investigated mechanisms by which AhR activation affects glucose metabolism.Methods: Glucose tolerance, insulin resistance, and expression of peroxisome proliferator–activated receptor-α (PPAR-α) and genes affecting glucose metabolism or fatty acid oxidation and clock gene rhythms were investigated in wild-type (WT) and AhR-deficient [knockout (KO)] mice. AhR agonists and small interfering RNA (siRNA) were used to examine the effect of AhR on PPAR-α expression and glycolysis in the liver cell line Hepa-1c1c7 (c7) and its c12 and c4 derivatives. Brain, muscle ARNT-like protein 1 (Bmal1) siRNA and Ahr or Bmal1 expression plasmids were used to analyze the effect of BMAL1 on PPAR-α expression in c7 cells.Results: KO mice displayed enhanced insulin sensitivity and improved glucose tolerance, accompanied by decreased PPAR-α and key gluconeogenic and fatty acid oxidation enzymes. AhR agonists increased PPAR-α expression in c7 cells. Both Ahr and Bmal1 siRNA reduced PPAR-α and metabolism genes. Moreover, rhythms of BMAL1 and blood glucose were altered in KO mice.Conclusions: These results indicate a link between AhR signaling, circadian rhythms, and glucose metabolism. Furthermore, hepatic activation of the PPAR-α pathway provides a mechanism underlying AhR-mediated insulin resistance.

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Crosstalk between the AHR signaling pathway and circadian rhythm

Cited by 55 publications

References 54 publications

Attenuation of myocardial injury in mice with functional deletion of the circadian rhythm gene mPer2

Attenuation of myocardial injury in mice with functional deletion of the circadian rhythm gene mPer2

MicroRNA‐132 suppresses autoimmune encephalomyelitis by inducing cholinergic anti‐inflammation: A new Ahr‐based exploration

Aryl Hydrocarbon Receptor Deficiency Enhances Insulin Sensitivity and Reduces PPAR-α Pathway Activity in Mice

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