Aryl Hydrocarbon Receptor Promotes IL-10 Expression in Inflammatory Macrophages Through Src-STAT3 Signaling Pathway

Zhu, Junmin; Luo, Li; Tian, Lixing; Yin, Shangqi; Ma, Xiaoyuan; Cheng, Siyao; Tang, Wanqi; Yu, Jing; Ma, Wei; Zhou, Xiaoying; Xia, Fan; Yang, Xue; Yan, Jun; Xu, Xiang; Lv, Chuanzhu; Liang, Huaping

doi:10.3389/fimmu.2018.02033

Cited by 119 publications

(90 citation statements)

References 56 publications

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“…IL1B, IL4, IL6, IL17, IL10, IL23, IL27, IFNγ, etc.). [19][20][21][22][23] Such modulation of the cytokine milieu within the lamina propria of the intestine dictates the pro-or suppressive phenotype with consequences affecting barrier integrity and the community structure of the microbiota. In addition to promoting epithelial xenobiotic metabolism, AHR activity within the crypt-villi axis of the gastrointestinal tract regulates epithelial cell differentiation and repair.…”

Section: Introductionmentioning

confidence: 99%

Intestinal microbiota-derived tryptophan metabolites are predictive of Ah receptor activity

et al. 2020

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Commensal microbiota-dependent tryptophan catabolism within the gastrointestinal tract is known to exert profound effects upon host physiology, including the maintenance of epithelial barrier and immune function. A number of abundant microbiota-derived tryptophan metabolites exhibit activation potential for the aryl hydrocarbon receptor (AHR). Gene expression facilitated by AHR activation through the presence of dietary or microbiota-generated metabolites can influence gastrointestinal homeostasis and confer protection from intestinal challenges. Utilizing untargeted mass spectrometry-based metabolomics profiling, combined with AHR activity screening assays, we identify four previously unrecognized tryptophan metabolites, present in mouse cecal contents and human stool, with the capacity to activate AHR. Using GC/MS and LC/MS platforms, quantification of these novel AHR activators, along with previously established AHR-activating tryptophan metabolites, was achieved, providing a relative order of abundance. Using physiologically relevant concentrations and quantitative gene expression analyses, the relative efficacy of these tryptophan metabolites with regard to mouse or human AHR activation potential is examined. These data reveal indole, 2-oxindole, indole-3-acetic acid and kynurenic acid as the dominant AHR activators in mouse cecal contents and human stool from participants on a controlled diet. Here we provide the first documentation of the relative abundance and AHR activation potential of a panel of microbiota-derived tryptophan metabolites. Furthermore, these data reveal the human AHR to be more sensitive, at physiologically relevant concentrations, to tryptophan metabolite activation than mouse AHR. Additionally, correlation analyses indicate a relationship linking major tryptophan metabolite abundance with AHR activity, suggesting these cecal/fecal metabolites represent biomarkers of intestinal AHR activity.

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Section: Introductionmentioning

confidence: 99%

Intestinal microbiota-derived tryptophan metabolites are predictive of Ah receptor activity

et al. 2020

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“…Another study showed that the indoleamine 2,3-dioxygenase (IDO) inhibitor 1methyl-tryptophan activated AhR responses in MSC (Lewis et al 2017). Further, research from Zhu et al (2018) found the AhR-Src-STAT3-IL-10 signaling pathway was critical in regulation of inflammatory macrophages.…”

Section: Discussionmentioning

confidence: 99%

Activation of aryl hydrocarbon receptor (AhR) in mesenchymal stem cells modulates macrophage polarization in asthma

Cui

Feng

et al. 2020

Journal of Immunotoxicology

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Macrophage polarization has been demonstrated to exert a vital role on asthma pathogenesis. Mesenchymal stem cells (MSC) have the capacity to modulate macrophage differentiation from a proinflammatory M1 phenotype toward an anti-inflammatory M2 phenotype. However, the impact of MSCmacrophage interactions on asthma development and underlying mechanisms responsible for this interaction remain largely unknown. The aim of this study was to investigate the role of AhR expressed on MSC in macrophage polarization in a cockroach extract (CRE)-induced asthma mouse model. The studies here revealed that MSC polarized macrophages from a pro-inflammatory M1 phenotype toward an antiinflammatory M2 phenotype in this model. The mRNA levels of interleukin (IL)-6, IL-1b, and NOS2 as M1 markers were significantly decreased while those of select M2 markers such as Arg-1, FIZZ1, and YM-1 were significantly enhanced. It was also observed that aryl hydrocarbon receptor (AhR) signaling was significantly increased during asthma pathogenesis as demonstrated by enhanced mRNA expression of AhR, CYP1a1, and CYP1b1. It was also seen that the elevated AhR signaling was able to attenuate the onset of asthma. Use of an AhR antagonist (CH223191) resulted in significant inhibition of the AhR signaling and increases in M2 marker expression, but led to elevation of expression of M1 markers in the CRE-induced asthma model. Taken together, the current study showed that MSC can modulate macrophage polarization, in part, via activation of AhR signaling during CRE-induced asthma.

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“…It has been shown that AhR enhances interleukin-10 (IL-10) production by macrophages, resulting in suppression of the inflammatory response [46], and that AhR activation promotes monocyte-derived dendritic cell (mo-DC) and inhibits monocyte-derived macrophage (mo-Mac) differentiation [47]. On the contrary, both AhR silencing and AhR pharmacological inhibition increased mo-Mac while decreasing mo-DC proportions.…”

Section: Discussionmentioning

confidence: 99%

Female AhR Knockout Mice Develop a Minor Renal Insufficiency in an Adenine-Diet Model of Chronic Kidney Disease

Makhloufi

Nicolas

McKay

et al. 2020

IJMS

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Cardiovascular complications observed in chronic kidney disease (CKD) are associated with aryl hydrocarbon receptor (AhR) activation by tryptophan-derived uremic toxins—mainly indoxyl sulfate (IS). AhR is a ligand-activated transcription factor originally characterized as a receptor of xenobiotics involved in detoxification. The aim of this study was to determine the role of AhR in a CKD mouse model based on an adenine diet. Wild-type (WT) and AhR−/− mice were fed by alternating an adenine-enriched diet and a regular diet for 6 weeks. Our results showed an increased mortality rate of AhR−/− males. AhR−/− females survived and developed a less severe renal insufficiency that WT mice, reflected by urea, creatinine, and IS measurement in serum. The protective effect was related to a decrease of pro-inflammatory and pro-fibrotic gene expression, an attenuation of tubular injury, and a decrease of 2,8-dihydroxyadenine crystal deposition in the kidneys of AhR−/− mice. These mice expressed low levels of xanthine dehydrogenase, which oxidizes adenine into 2,8-dihydroxyadenine, and low levels of the IS metabolism enzymes. In conclusion, the CKD model of adenine diet is not suitable for AhR knockout mice when studying the role of this transcription factor in cardiovascular complications, as observed in human CKD.

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Aryl Hydrocarbon Receptor Promotes IL-10 Expression in Inflammatory Macrophages Through Src-STAT3 Signaling Pathway

Cited by 119 publications

References 56 publications

Intestinal microbiota-derived tryptophan metabolites are predictive of Ah receptor activity

Intestinal microbiota-derived tryptophan metabolites are predictive of Ah receptor activity

Activation of aryl hydrocarbon receptor (AhR) in mesenchymal stem cells modulates macrophage polarization in asthma

Female AhR Knockout Mice Develop a Minor Renal Insufficiency in an Adenine-Diet Model of Chronic Kidney Disease

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