Shared epitope–aryl hydrocarbon receptor crosstalk underlies the mechanism of gene–environment interaction in autoimmune arthritis

Fu, Jiaqi; Nogueira, Sarah Veloso; Drongelen, Vincent van; Coit, Patrick; Ling, Song; Rosloniec, Edward F.; Sawalha, Amr H.; Holoshitz, Joseph

doi:10.1073/pnas.1722124115

Cited by 57 publications

(52 citation statements)

References 54 publications

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“…Rheumatoid arthritis (RA) severity has been linked to combination of the HLA-DRB1 amino acid sequence motif called "shared epitope" (SE) and cigarette smoking (CS) (1). Animal studies support the association of DRB1 alleles and CS with arthritis susceptibility (2,3) and highlight the involvement of IL-17 producing T helper cells (Th17) in the disease through the activation of the aryl hydrocarbon receptor (AhR). We have previously reported (4) on a limited group of donors that cigarette smoke extract (CSE) treatment of Th17 cells leads to reduced cytokine production and prevents normal differentiation of human Th17.…”

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confidence: 99%

Shared epitope is associated with the reactivity of Th17 cells to cigarette smoke extract regardless of smoking history

et al. 2019

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confidence: 99%

Shared epitope is associated with the reactivity of Th17 cells to cigarette smoke extract regardless of smoking history

et al. 2019

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“…TCDD also suppressed sensitization of mice to peanuts, at least in part by elevating the percentage of Treg cells, whereas FICZ did not increase this percentage or influence the cytokine production induced by peanut extract (Schulz et al 2012) (Table 1). However, both FICZ and TCDD enhanced the severity of collageninduced arthritis in transgenic, shared epitope (SE)-positive mice and elevated the numbers of cells expressing IL-17 both in popliteal lymph nodes and the spleen, without influencing the abundance of FoxP3 expressing cells (Fu et al 2018) (Table 1).…”

Section: Differentiation Of Immune Cells and Immune Responsesmentioning

confidence: 99%

“…Treatment of murine CD4 þ T cells originally expressing the proinflammatory IL-17 with 100 nM FICZ in the presence of TGFb caused these cells to acquire an anti-inflammatory phenotype (Gagliani et al 2015). Furthermore, when 100 nM FICZ or 100 nM TCDD was added in the presence of IL-27 and TGFb to murine CD4 þ T cells, these cells acquired an anti-inflammatory Tr1 phenotype, (Fu et al 2018) with enhanced secretion of the anti-inflammatory IL-10 (Apetoh et al 2010). In addition, expression of IL-10 by naïve human T cells was enhanced by differentiation in the presence of FICZ (Gandhi et al 2010).…”

Section: Differentiation Of Immune Cells and Immune Responsesmentioning

confidence: 99%

The tryptophan derivative 6-formylindolo[3,2-b]carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor signaling, balances cell growth and differentiation

Rannug

2018

Critical Reviews in Toxicology

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The aryl hydrocarbon receptor (AHR) is not essential to survival, but does act as a key regulator of many normal physiological events. The role of this receptor in toxicological processes has been studied extensively, primarily employing the high-affinity ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, regulation of physiological responses by endogenous AHR ligands remains to be elucidated. Here, we review developments in this field, with a focus on 6-formylindolo[3,2-b]carbazole (FICZ), the endogenous ligand with the highest affinity to the receptor reported to date. The binding of FICZ to different isoforms of the AHR seems to be evolutionarily well conserved and there is a feedback loop that controls AHR activity through metabolic degradation of FICZ via the highly inducible cytochrome P450 1A1. Several investigations provide strong evidence that FICZ plays a critical role in normal physiological processes and can ameliorate immune diseases with remarkable efficiency. Low levels of FICZ are pro-inflammatory, providing resistance to pathogenic bacteria, stimulating the anti-tumor functions, and promoting the differentiation of cancer cells by repressing genes in cancer stem cells. In contrast, at high concentrations FICZ behaves in a manner similar to TCDD, exhibiting toxicity toward fish and bird embryos, immune suppression, and activation of cancer progression. The findings are indicative of a dual role for endogenously activated AHR in barrier tissues, aiding clearance of infections and suppressing immunity to terminate a vicious cycle that might otherwise lead to disease. There is not much support for the AHR ligand-specific immune responses proposed, the differences between FICZ and TCDD in this context appear to be explained by the rapid metabolism of FICZ.

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“…9) gene has been suggestively associated with rheumatoid arthritis risk. Of importance, AHR activity has been associated with rheumatoid arthritis as well as with increased risk for rheumatoid arthritis in smokers; and AHR activity has been demonstrated to contribute to rheumatoid arthritis severity in animal models through the modulation of environmental stimuli (Nakahama et al, 2011;Kazantseva et al, 2012;Vogel et al, 2014;Fu et al, 2018).…”

Section: Snps Distant From Ahres Alter Ahr-regulated Gene Expressionmentioning

confidence: 99%

Single Nucleotide Polymorphisms at a Distance from Aryl Hydrocarbon Receptor (AHR) Binding Sites Influence AHR Ligand–Dependent Gene Expression

et al. 2019

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Greater than 90% of significant genome-wide association study (GWAS) single-nucleotide polymorphisms (SNPs) are in noncoding regions of the genome, but only 25.6% are known expression quantitative trait loci (eQTLs). Therefore, the function of many significant GWAS SNPs remains unclear. We have identified a novel type of eQTL for which SNPs distant from ligand-activated transcription factor (TF) binding sites can alter target gene expression in a SNP genotype-by-ligand-dependent fashion that we refer to as pharmacogenomic eQTLs (PGx-eQTLs)-loci that may have important pharmacotherapeutic implications. In the present study, we integrated chromatin immunoprecipitation-seq with RNA-seq and SNP genotype data for a panel of lymphoblastoid cell lines to identify 10 novel cis PGx-eQTLs dependent on the ligand-activated TF aryl hydrocarbon receptor (AHR)-a critical environmental sensor for xenobiotic (drug) and immune response. Those 10 cis PGx-eQTLs were eQTLs only after AHR ligand treatment, even though the SNPs did not create/destroy an AHR response element-the DNA sequence motif recognized and bound by AHR. Additional functional studies in multiple cell lines demonstrated that some cis PGx-eQTLs are functional in multiple cell types, whereas others displayed SNPby-ligand-dependent effects in just one cell type. Furthermore, four of those cis PGx-eQTLs had previously been associated with clinical phenotypes, indicating that those loci might have the potential to inform clinical decisions. Therefore, SNPs across the genome that are distant from TF binding sites for ligand-activated TFs might function as PGx-eQTLs and, as a result, might have important clinical implications for interindividual variation in drug response. SIGNIFICANCE STATEMENTMore than 90% of single-nucleotide polymorphisms (SNPs) that are associated with clinical phenotypes are located in noncoding regions of the genome. However, the mechanisms of action of many of those SNPs have not been elucidated, and drugs may unmask functional expression quantitative trail loci (eQTLs). In the current study, we used drugs that bind to the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and identified SNPs that were associated with interindividual variation in gene expression following drug exposure-termed pharmacogenomic (PGx)-eQTLs. Possibly of greater significance, those PGx-eQTL SNPs were outside of AHR binding sites, indicating that they do not interrupt AHR DNA recognition. PGx-eQTLs such as those described in this work may have crucial implications for interindividual variation in drug. allele frequency; PGx, pharmacogenomic; qPCR, quantitative polymerase chain reaction; qRT-PCR, quantitative reverse-transcription polymerase chain reaction; SNP, single-nucleotide polymorphism; TF, transcription factor. 984 Neavin et al.

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Shared epitope–aryl hydrocarbon receptor crosstalk underlies the mechanism of gene–environment interaction in autoimmune arthritis

Cited by 57 publications

References 54 publications

Shared epitope is associated with the reactivity of Th17 cells to cigarette smoke extract regardless of smoking history

Shared epitope is associated with the reactivity of Th17 cells to cigarette smoke extract regardless of smoking history

The tryptophan derivative 6-formylindolo[3,2-b]carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor signaling, balances cell growth and differentiation

Single Nucleotide Polymorphisms at a Distance from Aryl Hydrocarbon Receptor (AHR) Binding Sites Influence AHR Ligand–Dependent Gene Expression

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