Publications by authors named "David H Sherr"

68 Publications

The aryl hydrocarbon receptor suppresses immunity to oral squamous cell carcinoma through immune checkpoint regulation.

Proc Natl Acad Sci U S A 2021 May;118(19)

Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118;

Immune checkpoint inhibitors represent some of the most important cancer treatments developed in the last 20 y. However, existing immunotherapy approaches benefit only a minority of patients. Here, we provide evidence that the aryl hydrocarbon receptor (AhR) is a central player in the regulation of multiple immune checkpoints in oral squamous cell carcinoma (OSCC). Orthotopic transplant of mouse OSCC cells from which the AhR has been deleted (MOC1) results, within 1 wk, in the growth of small tumors that are then completely rejected within 2 wk, concomitant with an increase in activated T cells in tumor-draining lymph nodes (tdLNs) and T cell signaling within the tumor. By 2 wk, AhR control cells (MOC1), but not MOC1 cells up-regulate exhaustion pathways in the tumor-infiltrating T cells and expression of checkpoint molecules on CD4 T cells (PD-1, CTLA4, Lag3, and CD39) and macrophages, dendritic cells, and Ly6G myeloid cells (PD-L1 and CD39) in tdLNs. Notably, MOC1 cell transplant renders mice 100% immune to later challenge with wild-type tumors. Analysis of altered signaling pathways within MOC1 cells shows that the AhR controls baseline and IFNγ-induced and PD-L1 expression, the latter of which occurs through direct transcriptional control. These observations 1) confirm the importance of malignant cell AhR in suppression of tumor immunity, 2) demonstrate the involvement of the AhR in IFNγ control of PD-L1 and IDO expression in the cancer context, and 3) suggest that the AhR is a viable target for modulation of multiple immune checkpoints.
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http://dx.doi.org/10.1073/pnas.2012692118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126867PMC
May 2021

How the AHR Became Important in Cancer: The Role of Chronically Active AHR in Cancer Aggression.

Int J Mol Sci 2020 Dec 31;22(1). Epub 2020 Dec 31.

Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, USA.

For decades, the aryl hydrocarbon receptor (AHR) was studied for its role in environmental chemical toxicity i.e., as a quirk of nature and a mediator of unintended consequences of human pollution. During that period, it was not certain that the AHR had a "normal" physiological function. However, the ongoing accumulation of data from an ever-expanding variety of studies on cancer, cancer immunity, autoimmunity, organ development, and other areas bears witness to a staggering array of AHR-controlled normal and pathological activities. The objective of this review is to discuss how the AHR has gone from a likely contributor to genotoxic environmental carcinogen-induced cancer to a master regulator of malignant cell progression and cancer aggression. Particular focus is placed on the association between AHR activity and poor cancer outcomes, feedback loops that control chronic AHR activity in cancer, and the role of chronically active AHR in driving cancer cell invasion, migration, cancer stem cell characteristics, and survival.
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http://dx.doi.org/10.3390/ijms22010387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795223PMC
December 2020

Tolerogenic nanoparticles suppress central nervous system inflammation.

Proc Natl Acad Sci U S A 2020 12 25;117(50):32017-32028. Epub 2020 Nov 25.

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard University Medical School, Boston, MA 02115;

Therapeutic approaches for the induction of immune tolerance remain an unmet clinical need for the treatment of autoimmune diseases, including multiple sclerosis (MS). Based on its role in the control of the immune response, the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) is a candidate target for novel immunotherapies. Here, we report the development of AhR-activating nanoliposomes (NLPs) to induce antigen-specific tolerance. NLPs loaded with the AhR agonist ITE and a T cell epitope from myelin oligodendrocyte glycoprotein (MOG) induced tolerogenic dendritic cells and suppressed the development of experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS, in preventive and therapeutic setups. EAE suppression was associated with the expansion of MOG-specific FoxP3 regulatory T cells (Treg cells) and type 1 regulatory T cells (Tr1 cells), concomitant with a reduction in central nervous system-infiltrating effector T cells (Teff cells). Notably, NLPs induced bystander suppression in the EAE model established in C57BL/6 × SJL F1 mice. Moreover, NLPs ameliorated chronic progressive EAE in nonobese diabetic mice, a model which resembles some aspects of secondary progressive MS. In summary, these studies describe a platform for the therapeutic induction of antigen-specific tolerance in autoimmune diseases.
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http://dx.doi.org/10.1073/pnas.2016451117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749362PMC
December 2020

The Carcinogenome Project: In Vitro Gene Expression Profiling of Chemical Perturbations to Predict Long-Term Carcinogenicity.

Environ Health Perspect 2019 04;127(4):47002

1 Computational Biomedicine, Boston University School of Medicine , Boston, Massachusetts, USA.

Background: Most chemicals in commerce have not been evaluated for their carcinogenic potential. The de facto gold-standard approach to carcinogen testing adopts the 2-y rodent bioassay, a time-consuming and costly procedure. High-throughput in vitro assays are a promising alternative for addressing the limitations in carcinogen screening.

Objectives: We developed a screening process for predicting chemical carcinogenicity and genotoxicity and characterizing modes of actions (MoAs) using in vitro gene expression assays.

Methods: We generated a large toxicogenomics resource comprising [Formula: see text] expression profiles corresponding to 330 chemicals profiled in HepG2 (human hepatocellular carcinoma cell line) at multiple doses and replicates. Predictive models of carcinogenicity and genotoxicity were built using a random forest classifier. Differential pathway enrichment analysis was performed to identify pathways associated with carcinogen exposure. Signatures of carcinogenicity and genotoxicity were compared with external sources, including Drugmatrix and the Connectivity Map.

Results: Among profiles with sufficient bioactivity, our classifiers achieved 72.2% Area Under the ROC Curve (AUC) for predicting carcinogenicity and 82.3% AUC for predicting genotoxicity. Chemical bioactivity, as measured by the strength and reproducibility of the transcriptional response, was not significantly associated with long-term carcinogenicity in doses up to [Formula: see text]. However, sufficient bioactivity was necessary for a chemical to be used for prediction of carcinogenicity. Pathway enrichment analysis revealed pathways consistent with known pathways that drive cancer, including DNA damage and repair. The data is available at https://clue.io/CRCGN_ABC , and a portal for query and visualization of the results is accessible at https://carcinogenome.org .

Discussion: We demonstrated an in vitro screening approach using gene expression profiling to predict carcinogenicity and infer MoAs of chemical perturbations. https://doi.org/10.1289/EHP3986.
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http://dx.doi.org/10.1289/EHP3986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785232PMC
April 2019

Inflammatory breast cancer: Activation of the aryl hydrocarbon receptor and its target CYP1B1 correlates closely with Wnt5a/b-β-catenin signalling, the stem cell phenotype and disease progression.

J Adv Res 2019 Mar 8;16:75-86. Epub 2018 Dec 8.

Department of Zoology, Faculty of Science, Cairo University, Cairo University, Giza 12613, Egypt.

The aim of the present study was to evaluate the expression levels of the aryl hydrocarbon receptor (AHR) and its target gene and to correlate their expression with Wnt5a/b-β-catenin, the CD44/CD24 cancer stem cell (CSC) subset and factors associated with poor prognosis in inflammatory breast cancer (IBC) and non-IBC patients. The methods of analysis used were quantitative real-time PCR, western blotting, immunohistochemistry and flow cytometry. Compared to non-IBC tissues, IBC tissues exhibited the overexpression of AHR and its target gene/protein CYP1B1. and mRNA levels were associated with the poor clinical prognosis markers tumour grade, lymphovascular invasion, cell proliferation and lymph node metastasis. Furthermore, AHR expression correlated with the expression of Wnt5a/b and β-catenin signalling molecules, and mRNA expression was downregulated in the SUM149 human IBC cell line and the MDA-MB-231 non-IBC cell line upon inhibition of AHR. gene knockout (CRISPR-Cas9) inhibits and expression in the IBC cell line. The CD44/CD24 subset was significantly correlated with the expression of AHR, CYP1B1, Wnt5a/b and β-catenin in IBC tissues. The overexpression of AHR and its target CYP1B1 correlated with the expression of Wnt5a/b and β-catenin, CSCs, and poor clinical prognostic factors of IBC. Thus, targeting AHR and/or its downstream target molecules CYP1B1 and Wnt5a/b may represent a therapeutic approach for IBC.
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http://dx.doi.org/10.1016/j.jare.2018.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413307PMC
March 2019

Old Receptor, New Tricks-The Ever-Expanding Universe of Aryl Hydrocarbon Receptor Functions. Report from the 4th AHR Meeting, 29⁻31 August 2018 in Paris, France.

Int J Mol Sci 2018 Nov 15;19(11). Epub 2018 Nov 15.

Toxicologie Pharmacologie et Signalisation Cellulaire, INSERM UMR-S1124, 45 rue des Saints-Pères, 75006 Paris, France.

In a time where "translational" science has become a mantra in the biomedical field, it is reassuring when years of research into a biological phenomenon suddenly points towards novel prevention or therapeutic approaches to disease, thereby demonstrating once again that basic science and translational science are intimately linked. The studies on the aryl hydrocarbon receptor (AHR) discussed here provide a perfect example of how years of basic toxicological research on a molecule, whose normal physiological function remained a mystery for so long, has now yielded a treasure trove of actionable information on the development of targeted therapeutics. Examples are autoimmunity, metabolic imbalance, inflammatory skin and gastro-intestinal diseases, cancer, development and perhaps ageing. Indeed, the AHR field no longer asks, "What does this receptor do in the absence of xenobiotics?" It now asks, "What doesn't this receptor do?".
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http://dx.doi.org/10.3390/ijms19113603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274973PMC
November 2018

Heavy Metal Neurotoxicants Induce ALS-Linked TDP-43 Pathology.

Toxicol Sci 2019 01;167(1):105-115

Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118.

Heavy metals, such as lead, mercury, and selenium, have been epidemiologically linked with a risk of ALS, but a molecular mechanism proving the connection has not been shown. A screen of putative developmental neurotoxins demonstrated that heavy metals (lead, mercury, and tin) trigger accumulation of TDP-43 into nuclear granules with concomitant loss of diffuse nuclear TDP-43. Lead (Pb) and methyl mercury (MeHg) disrupt the homeostasis of TDP-43 in neurons, resulting in increased levels of transcript and increased splicing activity of TDP-43. TDP-43 homeostasis is tightly regulated, and positively or negatively altering its splicing-suppressive activity has been shown to be deleterious to neurons. These changes are associated with the liquid-liquid phase separation of TDP-43 into nuclear bodies. We show that lead directly facilitates phase separation of TDP-43 in a dose-dependent manner in vitro, possibly explaining the means by which lead treatment results in neuronal nuclear granules. Metal toxicants also triggered the accumulation of insoluble TDP-43 in cultured cells and in the cortices of exposed mice. These results provide novel evidence of a direct mechanistic link between heavy metals, which are a commonly cited environmental risk of ALS, and molecular changes in TDP-43, the primary pathological protein accumulating in ALS.
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http://dx.doi.org/10.1093/toxsci/kfy267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317426PMC
January 2019

Towards Resolving the Pro- and Anti-Tumor Effects of the Aryl Hydrocarbon Receptor.

Int J Mol Sci 2018 May 7;19(5). Epub 2018 May 7.

Department of Environmental Health, Boston University School of Public Health, 72 East Concord St., Boston, MA 02118, USA.

We have postulated that the aryl hydrocarbon receptor (AHR) drives the later, more lethal stages of some cancers when chronically activated by endogenous ligands. However, other studies have suggested that, under some circumstances, the AHR can oppose tumor aggression. Resolving this apparent contradiction is critical to the design of AHR-targeted cancer therapeutics. Molecular (siRNA, shRNA, AHR repressor, CRISPR-Cas9) and pharmacological (AHR inhibitors) approaches were used to confirm the hypothesis that AHR inhibition reduces human cancer cell invasion (irregular colony growth in 3D Matrigel cultures and Boyden chambers), migration (scratch wound assay) and metastasis (human cancer cell xenografts in zebrafish). Furthermore, these assays were used for a head-to-head comparison between AHR antagonists and agonists. AHR inhibition or knockdown/knockout consistently reduced human ER/PR/Her2 and inflammatory breast cancer cell invasion, migration, and metastasis. This was associated with a decrease in invasion-associated genes (e.g., , , Thrombospondin, ) and an increase in , previously associated with decreased tumor aggression. Paradoxically, AHR agonists (2,3,7,8-tetrachlorodibenzo--dioxin and/or 3,3′-diindolylmethane) similarly inhibited irregular colony formation in Matrigel and blocked metastasis in vivo but accelerated migration. These data demonstrate the complexity of modulating AHR activity in cancer while suggesting that AHR inhibitors, and, under some circumstances, AHR agonists, may be useful as cancer therapeutics.
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http://dx.doi.org/10.3390/ijms19051388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983651PMC
May 2018

Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages.

Cell Rep 2018 04;23(4):1099-1111

Department of Chemical and Biological Engineering, Tufts University, Medford, MA 02155, USA. Electronic address:

The gut microbiota plays a significant role in the progression of fatty liver disease; however, the mediators and their mechanisms remain to be elucidated. Comparing metabolite profile differences between germ-free and conventionally raised mice against differences between mice fed a low- and high-fat diet (HFD), we identified tryptamine and indole-3-acetate (I3A) as metabolites that depend on the microbiota and are depleted under a HFD. Both metabolites reduced fatty-acid- and LPS-stimulated production of pro-inflammatory cytokines in macrophages and inhibited the migration of cells toward a chemokine, with I3A exhibiting greater potency. In hepatocytes, I3A attenuated inflammatory responses under lipid loading and reduced the expression of fatty acid synthase and sterol regulatory element-binding protein-1c. These effects were abrogated in the presence of an aryl-hydrocarbon receptor (AhR) antagonist, indicating that the effects are AhR dependent. Our results suggest that gut microbiota could influence inflammatory responses in the liver through metabolites engaging host receptors.
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http://dx.doi.org/10.1016/j.celrep.2018.03.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392449PMC
April 2018

Notch and Aryl Hydrocarbon Receptor Signaling Impact Definitive Hematopoiesis from Human Pluripotent Stem Cells.

Stem Cells 2018 07 1;36(7):1004-1019. Epub 2018 Apr 1.

Section of Hematology and Oncology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

Induced pluripotent stem cells (iPSCs) stand to revolutionize the way we study human development, model disease, and eventually, treat patients. However, these cell sources produce progeny that retain embryonic and/or fetal characteristics. The failure to mature to definitive, adult-type cells is a major barrier for iPSC-based disease modeling and drug discovery. To directly address these concerns, we have developed a chemically defined, serum and feeder-free-directed differentiation platform to generate hematopoietic stem-progenitor cells (HSPCs) and resultant adult-type progeny from iPSCs. This system allows for strict control of signaling pathways over time through growth factor and/or small molecule modulation. Through direct comparison with our previously described protocol for the production of primitive wave hematopoietic cells, we demonstrate that induced HSPCs are enhanced for erythroid and myeloid colony forming potential, and strikingly, resultant erythroid-lineage cells display enhanced expression of adult β globin indicating definitive pathway patterning. Using this system, we demonstrate the stage-specific roles of two key signaling pathways, Notch and the aryl hydrocarbon receptor (AHR), in the derivation of definitive hematopoietic cells. We illustrate the stage-specific necessity of Notch signaling in the emergence of hematopoietic progenitors and downstream definitive, adult-type erythroblasts. We also show that genetic or small molecule inhibition of the AHR results in the increased production of CD34 CD45 HSPCs while conversely, activation of the same receptor results in a block of hematopoietic cell emergence. Results presented here should have broad implications for hematopoietic stem cell transplantation and future clinical translation of iPSC-derived blood cells. Stem Cells 2018;36:1004-1019.
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http://dx.doi.org/10.1002/stem.2822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099224PMC
July 2018

Detection of aryl hydrocarbon receptor agonists in human samples.

Sci Rep 2018 03 21;8(1):4970. Epub 2018 Mar 21.

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor with important functions in the immune response and cancer. AHR agonists are provided by the environment, the commensal flora and the metabolism. Considering AHR physiological functions, AHR agonists may have important effects on health and disease. Thus, the quantification of AHR agonists in biological samples is of scientific and clinical relevance. We compared different reporter systems for the detection of AHR agonists in serum samples of Multiple Sclerosis (MS) patients, and assessed the influence of transfection methods and cell lines in a reporter-based in vitro assay. While the use of stable or transient reporters did not influence the measurement of AHR agonistic activity, the species of the cell lines used in these reporter assays had important effects on the reporter readings. These observations suggest that cell-specific factors influence AHR activation and signaling. Thus, based on the reported species selectivity of AHR ligands and the cell species-of-origin effects that we describe in this manuscript, the use of human cell lines is encouraged for the analysis of AHR agonistic activity in human samples. These findings may be relevant for the analysis of AHR agonists in human samples in the context of inflammatory and neoplastic disorders.
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http://dx.doi.org/10.1038/s41598-018-23323-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862868PMC
March 2018

Targeting STUB1-tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk.

Sci Transl Med 2017 Nov;9(417)

Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.

Chronic kidney disease (CKD/uremia) remains vexing because it increases the risk of atherothrombosis and is also associated with bleeding complications on standard antithrombotic/antiplatelet therapies. Although the associations of indolic uremic solutes and vascular wall proteins [such as tissue factor (TF) and aryl hydrocarbon receptor (AHR)] are being defined, the specific mechanisms that drive the thrombotic and bleeding risks are not fully understood. We now present an indolic solute-specific animal model, which focuses on solute-protein interactions and shows that indolic solutes mediate the hyperthrombotic phenotype across all CKD stages in an AHR- and TF-dependent manner. We further demonstrate that AHR regulates TF through STIP1 homology and U-box-containing protein 1 (STUB1). As a ubiquitin ligase, STUB1 dynamically interacts with and degrades TF through ubiquitination in the uremic milieu. TF regulation by STUB1 is supported in humans by an inverse relationship of STUB1 and TF expression and reduced STUB1-TF interaction in uremic vessels. Genetic or pharmacological manipulation of STUB1 in vascular smooth muscle cells inhibited thrombosis in flow loops. STUB1 perturbations reverted the uremic hyperthrombotic phenotype without prolonging the bleeding time, in contrast to heparin, the standard-of-care antithrombotic in CKD patients. Our work refines the thrombosis axis (STUB1 is a mediator of indolic solute-AHR-TF axis) and expands the understanding of the interconnected relationships driving the fragile thrombotic state in CKD. It also establishes a means of minimizing the uremic hyperthrombotic phenotype without altering the hemostatic balance, a long-sought-after combination in CKD patients.
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http://dx.doi.org/10.1126/scitranslmed.aam8475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854487PMC
November 2017

Dioxins and related environmental contaminants increase TDP-43 levels.

Mol Neurodegener 2017 05 5;12(1):35. Epub 2017 May 5.

Department of Pharmacology, Boston University School of Medicine, 72 East Concord St., R614, Boston, MA, 02118-2526, USA.

Background: Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative condition that is characterized by progressive loss of motor neurons and the accumulation of aggregated TAR DNA Binding Protein-43 (TDP-43, gene: TARDBP). Increasing evidence indicates that environmental factors contribute to the risk of ALS. Dioxins, related planar polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs) are environmental contaminants that activate the aryl hydrocarbon receptor (AHR), a ligand-activated, PAS family transcription factor. Recently, exposure to these toxicants was identified as a risk factor for ALS.

Methods: We examined levels of TDP-43 reporter activity, transcript and protein. Quantification was done using cell lines, induced pluripotent stem cells (iPSCs) and mouse brain. The target samples were treated with AHR agonists, including 6-Formylindolo[3,2-b]carbazole (FICZ, a potential endogenous ligand, 2,3,7,8-tetrachlorodibenzo(p)dioxin, and benzo(a)pyrene, an abundant carcinogen in cigarette smoke). The action of the agonists was inhibited by concomitant addition of AHR antagonists or by AHR-specific shRNA.

Results: We now report that AHR agonists induce up to a 3-fold increase in TDP-43 protein in human neuronal cell lines (BE-M17 cells), motor neuron differentiated iPSCs, and in murine brain. Chronic treatment with AHR agonists elicits over 2-fold accumulation of soluble and insoluble TDP-43, primarily because of reduced TDP-43 catabolism. AHR antagonists or AHR knockdown inhibits agonist-induced increases in TDP-43 protein and TARDBP transcription demonstrating that the ligands act through the AHR.

Conclusions: These results provide the first evidence that environmental AHR ligands increase TDP-43, which is the principle pathological protein associated with ALS. These results suggest novel molecular mechanisms through which a variety of prevalent environmental factors might directly contribute to ALS. The widespread distribution of dioxins, PCBs and PAHs is considered to be a risk factor for cancer and autoimmune diseases, but could also be a significant public health concern for ALS.
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http://dx.doi.org/10.1186/s13024-017-0177-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420162PMC
May 2017

Network-based analysis of transcriptional profiles from chemical perturbations experiments.

BMC Bioinformatics 2017 Mar 23;18(Suppl 5):130. Epub 2017 Mar 23.

Division of Computational Biomedicine, Boston University School of Medicine, 72 E Concord St, Boston, 02118, USA.

Background: Methods for inference and comparison of biological networks are emerging as powerful tools for the identification of groups of tightly connected genes whose activity may be altered during disease progression or due to chemical perturbations. Connectivity-based comparisons help identify aggregate changes that would be difficult to detect with differential analysis methods comparing individual genes.

Methods: In this study, we describe a pipeline for network comparison and its application to the analysis of gene expression datasets from chemical perturbation experiments, with the goal of elucidating the modes of actions of the profiled perturbations. We apply our pipeline to the analysis of the DrugMatrix and the TG-GATEs, two of the largest toxicogenomics resources available, containing gene expression measurements for model organisms exposed to hundreds of chemical compounds with varying carcinogenicity and genotoxicity.

Results: Starting from chemical-specific transcriptional networks inferred from these data, we show that the proposed comparative analysis of their associated networks identifies groups of chemicals with similar functions and similar carcinogenicity/genotoxicity profiles. We also show that the in-silico annotation by pathway enrichment analysis of the gene modules with a significant gain or loss of connectivity for specific groups of compounds can reveal molecular pathways significantly associated with the chemical perturbations and their likely modes of action.

Conclusions: The proposed pipeline for transcriptional network inference and comparison is highly reproducible and allows grouping chemicals with similar functions and carcinogenicity/genotoxicity profiles. In the context of drug discovery or drug repositioning, the methods presented here could help assign new functions to novel or existing drugs, based on the similarity of their associated network with those built for other known compounds. Additionally, the method has broad applicability beyond the uses here described and could be used as an alternative or as a complement to standard approaches of differential gene expression analysis.
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http://dx.doi.org/10.1186/s12859-017-1536-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374700PMC
March 2017

An Aryl Hydrocarbon Receptor-Mediated Amplification Loop That Enforces Cell Migration in ER-/PR-/Her2- Human Breast Cancer Cells.

Mol Pharmacol 2016 Nov 29;90(5):674-688. Epub 2016 Aug 29.

Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (O.N., Z.W., E.A.S., A.J.P., A.R.-C., D.H.S.); Boston University Molecular and Translational Medicine Program, Boston, Massachusetts (O.N., E.A.S.); Department of Medicine, Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts (D.G., A.L., S.Mo.); Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts (E.L., I.L., C.S.-R.); and Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts (S.Ma., K.L.)

The endogenous ligand-activated aryl hydrocarbon receptor (AHR) plays an important role in numerous biologic processes. As the known number of AHR-mediated processes grows, so too does the importance of determining what endogenous AHR ligands are produced, how their production is regulated, and what biologic consequences ensue. Consequently, our studies were designed primarily to determine whether ER/PR/Her2 breast cancer cells have the potential to produce endogenous AHR ligands and, if so, how production of these ligands is controlled. We postulated that: 1) malignant cells produce tryptophan-derived AHR ligand(s) through the kynurenine pathway; 2) these metabolites have the potential to drive AHR-dependent breast cancer migration; 3) the AHR controls expression of a rate-limiting kynurenine pathway enzyme(s) in a closed amplification loop; and 4) environmental AHR ligands mimic the effects of endogenous ligands. Data presented in this work indicate that primary human breast cancers, and their metastases, express high levels of AHR and tryptophan-2,3-dioxygenase (TDO); representative ER/PR/Her2 cell lines express TDO and produce sufficient intracellular kynurenine and xanthurenic acid concentrations to chronically activate the AHR. TDO overexpression, or excess kynurenine or xanthurenic acid, accelerates migration in an AHR-dependent fashion. Environmental AHR ligands 2,3,7,8-tetrachlorodibenzo[p]dioxin and benzo[a]pyrene mimic this effect. AHR knockdown or inhibition significantly reduces TDO2 expression. These studies identify, for the first time, a positive amplification loop in which AHR-dependent TDO2 expression contributes to endogenous AHR ligand production. The net biologic effect of AHR activation by endogenous ligands, which can be mimicked by environmental ligands, is an increase in tumor cell migration, a measure of tumor aggressiveness.
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http://dx.doi.org/10.1124/mol.116.105361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074452PMC
November 2016

A network based approach to drug repositioning identifies plausible candidates for breast cancer and prostate cancer.

BMC Med Genomics 2016 07 30;9(1):51. Epub 2016 Jul 30.

Bioinformatics Program, College of Engineering, Boston University, Boston, MA, USA.

Background: The high cost and the long time required to bring drugs into commerce is driving efforts to repurpose FDA approved drugs-to find new uses for which they weren't intended, and to thereby reduce the overall cost of commercialization, and shorten the lag between drug discovery and availability. We report on the development, testing and application of a promising new approach to repositioning.

Methods: Our approach is based on mining a human functional linkage network for inversely correlated modules of drug and disease gene targets. The method takes account of multiple information sources, including gene mutation, gene expression, and functional connectivity and proximity of within module genes.

Results: The method was used to identify candidates for treating breast and prostate cancer. We found that (i) the recall rate for FDA approved drugs for breast (prostate) cancer is 20/20 (10/11), while the rates for drugs in clinical trials were 131/154 and 82/106; (ii) the ROC/AUC performance substantially exceeds that of comparable methods; (iii) preliminary in vitro studies indicate that 5/5 candidates have therapeutic indices superior to that of Doxorubicin in MCF7 and SUM149 cancer cell lines. We briefly discuss the biological plausibility of the candidates at a molecular level in the context of the biological processes that they mediate.

Conclusions: Our method appears to offer promise for the identification of multi-targeted drug candidates that can correct aberrant cellular functions. In particular the computational performance exceeded that of other CMap-based methods, and in vitro experiments indicate that 5/5 candidates have therapeutic indices superior to that of Doxorubicin in MCF7 and SUM149 cancer cell lines. The approach has the potential to provide a more efficient drug discovery pipeline.
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http://dx.doi.org/10.1186/s12920-016-0212-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967295PMC
July 2016

Genome Editing of the CYP1A1 Locus in iPSCs as a Platform to Map AHR Expression throughout Human Development.

Stem Cells Int 2016 11;2016:2574152. Epub 2016 Apr 11.

Section of Hematology and Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; Center for Regenerative Medicine (CReM), Boston University and Boston Medical Center, Boston, MA 02118, USA.

The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that increases the expression of detoxifying enzymes upon ligand stimulation. Recent studies now suggest that novel endogenous roles of the AHR exist throughout development. In an effort to create an optimized model system for the study of AHR signaling in several cellular lineages, we have employed a CRISPR/CAS9 genome editing strategy in induced pluripotent stem cells (iPSCs) to incorporate a reporter cassette at the transcription start site of one of its canonical targets, cytochrome P450 1A1 (CYP1A1). This cell line faithfully reports on CYP1A1 expression, with luciferase levels as its functional readout, when treated with an endogenous AHR ligand (FICZ) at escalating doses. iPSC-derived fibroblast-like cells respond to acute exposure to environmental and endogenous AHR ligands, and iPSC-derived hepatocytes increase CYP1A1 in a similar manner to primary hepatocytes. This cell line is an important innovation that can be used to map AHR activity in discrete cellular subsets throughout developmental ontogeny. As further endogenous ligands are proposed, this line can be used to screen for safety and efficacy and can report on the ability of small molecules to regulate critical cellular processes by modulating the activity of the AHR.
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http://dx.doi.org/10.1155/2016/2574152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4842384PMC
May 2016

Role for the Aryl Hydrocarbon Receptor and Diverse Ligands in Oral Squamous Cell Carcinoma Migration and Tumorigenesis.

Mol Cancer Res 2016 08 29;14(8):696-706. Epub 2016 Apr 29.

Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts.

Unlabelled: Over 45,000 new cases of oral and pharyngeal cancers are diagnosed and account for over 8,000 deaths a year in the United States. An environmental chemical receptor, the aryl hydrocarbon receptor (AhR), has previously been implicated in oral squamous cell carcinoma (OSCC) initiation as well as in normal tissue-specific stem cell self-renewal. These previous studies inspired the hypothesis that the AhR plays a role in both the acquisition and progression of OSCC, as well as in the formation and maintenance of cancer stem-like cells. To test this hypothesis, AhR activity in two oral squamous cell lines was modulated with AhR prototypic, environmental and bacterial AhR ligands, AhR-specific inhibitors, and phenotypic, genomic and functional characteristics were evaluated. The data demonstrate that: (i) primary OSCC tissue expresses elevated levels of nuclear AhR as compared with normal tissue, (ii) AhR mRNA expression is upregulated in 320 primary OSCCs, (iii) AhR hyperactivation with several ligands, including environmental and bacterial ligands, significantly increases AhR activity, ALDH1 activity, and accelerates cell migration, (iv) AhR inhibition blocks the rapid migration of OSCC cells and reduces cell chemoresistance, (v) AhR knockdown inhibits tumorsphere formation in low adherence conditions, and (vi) AhR knockdown inhibits tumor growth and increases overall survival in vivo These data demonstrate that the AhR plays an important role in development and progression of OSCC, and specifically cancer stem-like cells. Prototypic, environmental, and bacterial AhR ligands may exacerbate OSCC by enhancing expression of these properties.

Implications: This study, for the first time, demonstrates the ability of diverse AhR ligands to regulate AhR activity in oral squamous cell carcinoma cells, as well as regulate several important characteristics of oral cancer stem cells, in vivo and in vitro Mol Cancer Res; 14(8); 696-706. ©2016 AACR.
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http://dx.doi.org/10.1158/1541-7786.MCR-16-0069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987205PMC
August 2016

The role of the aryl hydrocarbon receptor in the development of cells with the molecular and functional characteristics of cancer stem-like cells.

BMC Biol 2016 Mar 16;14:20. Epub 2016 Mar 16.

Department of Environmental Health, Boston University School of Public Health, 72 East Concord Street (R-408), Boston, Massachusetts, 02118, USA.

Background: Self-renewing, chemoresistant breast cancer stem cells are believed to contribute significantly to cancer invasion, migration and patient relapse. Therefore, the identification of signaling pathways that regulate the acquisition of stem-like qualities is an important step towards understanding why patients relapse and towards development of novel therapeutics that specifically target cancer stem cell vulnerabilities. Recent studies identified a role for the aryl hydrocarbon receptor (AHR), an environmental carcinogen receptor implicated in cancer initiation, in normal tissue-specific stem cell self-renewal. These studies inspired the hypothesis that the AHR plays a role in the acquisition of cancer stem cell-like qualities.

Results: To test this hypothesis, AHR activity in Hs578T triple negative and SUM149 inflammatory breast cancer cells were modulated with AHR ligands, shRNA or AHR-specific inhibitors, and phenotypic, genomic and functional stem cell-associated characteristics were evaluated. The data demonstrate that (1) ALDH(high) cells express elevated levels of Ahr and Cyp1b1 and Cyp1a1, AHR-driven genes, (2) AHR knockdown reduces ALDH activity by 80%, (3) AHR hyper-activation with several ligands, including environmental ligands, significantly increases ALDH1 activity, expression of stem cell- and invasion/migration-associated genes, and accelerates cell migration, (4) a significant correlation between Ahr or Cyp1b1 expression (as a surrogate marker for AHR activity) and expression of stem cell- and invasion/migration-associated gene sets is seen with genomic data obtained from 79 human breast cancer cell lines and over 1,850 primary human breast cancers, (5) the AHR interacts directly with Sox2, a master regulator of self-renewal; AHR ligands increase this interaction and nuclear SOX2 translocation, (6) AHR knockdown inhibits tumorsphere formation in low adherence conditions, (7) AHR inhibition blocks the rapid migration of ALDH(high) cells and reduces ALDH(high) cell chemoresistance, (8) ALDH(high) cells are highly efficient at initiating tumors in orthotopic xenografts, and (9) AHR knockdown inhibits tumor initiation and reduces tumor Aldh1a1, Sox2, and Cyp1b1 expression in vivo.

Conclusions: These data suggest that the AHR plays an important role in development of cells with cancer stem cell-like qualities and that environmental AHR ligands may exacerbate breast cancer by enhancing expression of these properties.
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http://dx.doi.org/10.1186/s12915-016-0240-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794823PMC
March 2016

Life-Long Implications of Developmental Exposure to Environmental Stressors: New Perspectives.

Endocrinology 2015 Oct 4;156(10):3408-15. Epub 2015 Aug 4.

Departments of Environmental Health (P.G., D.C.B.) and Nutrition (Q.S.), Harvard T.H. Chan School of Public Health; Children's Hospital (D.C.B.), Harvard Medical School; and Channing Division of Network Medicine (Q.S.), Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115; Department of Environmental Medicine (P.G.), Institute of Public Health, University of Southern Denmark, 5000 Odense, Denmark; Institut National de la Santé et de la Recherche Médicale unit 1124 (R.B.), Université Paris Descartes, Hôpital Necker enfants malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France; University of Leuven (L.C.), Center for Human Genetics, 3000 Leuven, Belgium; Division of Extramural Research and Training (L.H.C., K.A.G., W.S., J.J.H.), National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; Institut National de la Santé et de la Recherche Médicale, Unit 1085 (S.C.), University Rennes I, F-35000 Rennes, France; Joseph J. Zilber School of Public Health (R.A.E.), University of Wisconsin, Milwaukee, Wisconsin 53201; Department of Preventive Medicine (E.-H.H.), School of Medicine, Ewha Womans University, Seoul 158-710, Republic of Korea; Institut National de la Recherche Agronomique (C.J.), MR Unité Mixte de Recherche 1198 Biologie du Développement et Reproduction, F-78350 Jouy-en-Josas, France; Université Versailles-St-Quentin (C.J.), 78000 Versailles, France; Children's Environmental Health and Disease Prevention Research Center and Department of Epidemiology, Geisel School of Medicine at Dartmouth (M.K.), Hanover, New Hampshire 03766; Department of Environmental Health (T.K.), University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan; Department of Environmental Medicine (B.P.L.), University of Rochester School of Medicine and Dentistry, Rochester, New York 14642; Department of Environmental Health Sciences and Columbia Center for Children's Environmental Heal

The Developmental Origins of Health and Disease (DOHaD) paradigm is one of the most rapidly expanding areas of biomedical research. Environmental stressors that can impact on DOHaD encompass a variety of environmental and occupational hazards as well as deficiency and oversupply of nutrients and energy. They can disrupt early developmental processes and lead to increased susceptibility to disease/dysfunctions later in life. Presentations at the fourth Conference on Prenatal Programming and Toxicity in Boston, in October 2014, provided important insights and led to new recommendations for research and public health action. The conference highlighted vulnerable exposure windows that can occur as early as the preconception period and epigenetics as a major mechanism than can lead to disadvantageous "reprogramming" of the genome, thereby potentially resulting in transgenerational effects. Stem cells can also be targets of environmental stressors, thus paving another way for effects that may last a lifetime. Current testing paradigms do not allow proper characterization of risk factors and their interactions. Thus, relevant exposure levels and combinations for testing must be identified from human exposure situations and outcome assessments. Testing of potential underpinning mechanisms and biomarker development require laboratory animal models and in vitro approaches. Only few large-scale birth cohorts exist, and collaboration between birth cohorts on a global scale should be facilitated. DOHaD-based research has a crucial role in establishing factors leading to detrimental outcomes and developing early preventative/remediation strategies to combat these risks.
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http://dx.doi.org/10.1210/EN.2015-1350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588822PMC
October 2015

The Aryl Hydrocarbon Receptor is a Critical Regulator of Tissue Factor Stability and an Antithrombotic Target in Uremia.

J Am Soc Nephrol 2016 Jan 27;27(1):189-201. Epub 2015 May 27.

Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts;

Patients with CKD suffer high rates of thrombosis, particularly after endovascular interventions, yet few options are available to improve management and reduce thrombotic risk. We recently demonstrated that indoxyl sulfate (IS) is a potent CKD-specific prothrombotic metabolite that induces tissue factor (TF) in vascular smooth muscle cells (vSMCs), although the precise mechanism and treatment implications remain unclear. Because IS is an agonist of the aryl hydrocarbon receptor (AHR), we first examined the relationship between IS levels and AHR-inducing activity in sera of patients with ESRD. IS levels correlated significantly with both vSMC AHR activity and TF activity. Mechanistically, we demonstrated that IS activates the AHR pathway in primary human aortic vSMCs, and further, that AHR interacts directly with and stabilizes functional TF. Antagonists directly targeting AHR enhanced TF ubiquitination and degradation and suppressed thrombosis in a postinterventional model of CKD and endovascular injury. Furthermore, AHR antagonists inhibited TF in a manner dependent on circulating IS levels. In conclusion, we demonstrated that IS regulates TF stability through AHR signaling and uncovered AHR as an antithrombotic target and AHR antagonists as a novel class of antithrombotics. Together, IS and AHR have potential as uremia-specific biomarkers and targets that may be leveraged as a promising theranostic platform to better manage the elevated thrombosis rates in patients with CKD.
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http://dx.doi.org/10.1681/ASN.2014121241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696580PMC
January 2016

In silico identification of an aryl hydrocarbon receptor antagonist with biological activity in vitro and in vivo.

Mol Pharmacol 2014 Nov 26;86(5):593-608. Epub 2014 Aug 26.

Molecular Medicine Program, Boston University School of Medicine, Boston, Massachusetts (A.J.P., E.A.S., O.N.); Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts (A.J.P., E.A.S., O.N., S.N., J.J.S., DHS); Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts (M.P.P., T.G.H.); Department of Chemistry, Boston University (T.D.A.); Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts (M.E.H., D.G.F.); Wake Forest Innovations, Wake Forest University, Winston-Salem, North Carolina (S.E.H.); and Biomedical Engineering, Boston University, Boston, Massachusetts (D.K., D.B., S.V.)

The aryl hydrocarbon receptor (AHR) is critically involved in several physiologic processes, including cancer progression and multiple immune system activities. We, and others, have hypothesized that AHR modulators represent an important new class of targeted therapeutics. Here, ligand shape-based virtual modeling techniques were used to identify novel AHR ligands on the basis of previously identified chemotypes. Four structurally unique compounds were identified. One lead compound, 2-((2-(5-bromofuran-2-yl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (CB7993113), was further tested for its ability to block three AHR-dependent biologic activities: triple-negative breast cancer cell invasion or migration in vitro and AHR ligand-induced bone marrow toxicity in vivo. CB7993113 directly bound both murine and human AHR and inhibited polycyclic aromatic hydrocarbon (PAH)- and TCDD-induced reporter activity by 75% and 90% respectively. A novel homology model, comprehensive agonist and inhibitor titration experiments, and AHR localization studies were consistent with competitive antagonism and blockade of nuclear translocation as the primary mechanism of action. CB7993113 (IC50 3.3 × 10(-7) M) effectively reduced invasion of human breast cancer cells in three-dimensional cultures and blocked tumor cell migration in two-dimensional cultures without significantly affecting cell viability or proliferation. Finally, CB7993113 effectively inhibited the bone marrow ablative effects of 7,12-dimethylbenz[a]anthracene in vivo, demonstrating drug absorption and tissue distribution leading to pharmacological efficacy. These experiments suggest that AHR antagonists such as CB7993113 may represent a new class of targeted therapeutics for immunomodulation and/or cancer therapy.
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http://dx.doi.org/10.1124/mol.114.093369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201140PMC
November 2014

Genomic models of short-term exposure accurately predict long-term chemical carcinogenicity and identify putative mechanisms of action.

PLoS One 2014 24;9(7):e102579. Epub 2014 Jul 24.

Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America; Department of Computational Biomedicine, Boston University Medical Campus, Boston, Massachusetts, United States of America.

Background: Despite an overall decrease in incidence of and mortality from cancer, about 40% of Americans will be diagnosed with the disease in their lifetime, and around 20% will die of it. Current approaches to test carcinogenic chemicals adopt the 2-year rodent bioassay, which is costly and time-consuming. As a result, fewer than 2% of the chemicals on the market have actually been tested. However, evidence accumulated to date suggests that gene expression profiles from model organisms exposed to chemical compounds reflect underlying mechanisms of action, and that these toxicogenomic models could be used in the prediction of chemical carcinogenicity.

Results: In this study, we used a rat-based microarray dataset from the NTP DrugMatrix Database to test the ability of toxicogenomics to model carcinogenicity. We analyzed 1,221 gene-expression profiles obtained from rats treated with 127 well-characterized compounds, including genotoxic and non-genotoxic carcinogens. We built a classifier that predicts a chemical's carcinogenic potential with an AUC of 0.78, and validated it on an independent dataset from the Japanese Toxicogenomics Project consisting of 2,065 profiles from 72 compounds. Finally, we identified differentially expressed genes associated with chemical carcinogenesis, and developed novel data-driven approaches for the molecular characterization of the response to chemical stressors.

Conclusion: Here, we validate a toxicogenomic approach to predict carcinogenicity and provide strong evidence that, with a larger set of compounds, we should be able to improve the sensitivity and specificity of the predictions. We found that the prediction of carcinogenicity is tissue-dependent and that the results also confirm and expand upon previous studies implicating DNA damage, the peroxisome proliferator-activated receptor, the aryl hydrocarbon receptor, and regenerative pathology in the response to carcinogen exposure.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0102579PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109923PMC
April 2015

Identification of cinnabarinic acid as a novel endogenous aryl hydrocarbon receptor ligand that drives IL-22 production.

PLoS One 2014 3;9(2):e87877. Epub 2014 Feb 3.

Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.

The aryl hydrocarbon receptor (AHR) binds to environmental toxicants including synthetic halogenated aromatic hydrocarbons and is involved in a diverse array of biological processes. Recently, the AHR was shown to control host immunity by affecting the balance between inflammatory T cells that produce IL-17 (Th17) and IL-22 versus regulatory T cells (Treg) involved in tolerance. While environmental AHR ligands can mediate this effect, endogenous ligands are likely to be more relevant in host immune responses. We investigated downstream metabolites of tryptophan as potential AHR ligands because (1) tryptophan metabolites have been implicated in regulating the balance between Th17 and Treg cells and (2) many of the AHR ligands identified thus far are derivatives of tryptophan. We characterized the ability of tryptophan metabolites to bind and activate the AHR and to increase IL-22 production in human T cells. We report that the tryptophan metabolite, cinnabarinic acid (CA), is an AHR ligand that stimulates the differentiation of human and mouse T cells producing IL-22. We compare the IL-22-stimulating activity of CA to that of other tryptophan metabolites and define stimulation conditions that lead to CA production from immune cells. Our findings link tryptophan metabolism to AHR activation and define a novel endogenous AHR agonist with potentially broad biological functions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087877PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3912126PMC
October 2014

The role of the aryl hydrocarbon receptor in normal and malignant B cell development.

Semin Immunopathol 2013 Nov 13;35(6):705-16. Epub 2013 Aug 13.

Department of Environmental Health, Boston University School of Public Health, 72 East Concord Street (R-408), Boston, MA, 02118, USA,

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor historically studied for its role in environmental chemical-mediated toxicity and carcinogenicity. In the last 5 years, however, it has become clear that the AhR, presumably activated by endogenous ligand(s), plays an important role in immune system development and function. Other articles in this edition summarize AhR function during T cell and antigen-presenting cell development and function, including the effects of AhR activation on dendritic cell function, T cell skewing, inflammation, and autoimmune disease. Here, we focus on AhR expression and function during B cell differentiation. Studies exploiting immunosuppressive environmental chemicals to probe the role of the AhR in humoral immunity are also reviewed to illustrate the multiple levels at which a "nominally activated" AhR could control B cell differentiation from the hematopoietic stem cell through the pro-B cell, mature B cell, and antibody-secreting plasma cell stages. Finally, a putative role for the AhR in the basic biology of B cell malignancies, many of which have been associated with exposure to environmental AhR ligands, is discussed.
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http://dx.doi.org/10.1007/s00281-013-0390-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824572PMC
November 2013

Aryl hydrocarbon receptor control of adaptive immunity.

Pharmacol Rev 2013 1;65(4):1148-61. Epub 2013 Aug 1.

Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that belongs to the family of basic helix-loop-helix transcription factors. Although the AhR was initially recognized as the receptor mediating the pathologic effects of dioxins and other pollutants, the activation of AhR by endogenous and environmental factors has important physiologic effects, including the regulation of the immune response. Thus, the AhR provides a molecular pathway through which environmental factors modulate the immune response in health and disease. In this review, we discuss the role of AhR in the regulation of the immune response, the source and chemical nature of AhR ligands, factors controlling production and degradation of AhR ligands, and the potential to target the AhR for therapeutic immunomodulation.
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http://dx.doi.org/10.1124/pr.113.007823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799235PMC
February 2014

The aryl hydrocarbon receptor directs hematopoietic progenitor cell expansion and differentiation.

Blood 2013 Jul 30;122(3):376-85. Epub 2013 May 30.

Section of Hematology and Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.

The evolutionarily conserved aryl hydrocarbon receptor (AhR) has been studied for its role in environmental chemical-induced toxicity. However, recent studies have demonstrated that the AhR may regulate the hematopoietic and immune systems during development in a cell-specific manner. These results, together with the absence of an in vitro model system enabling production of large numbers of primary human hematopoietic progenitor cells (HPs) capable of differentiating into megakaryocyte- and erythroid-lineage cells, motivated us to determine if AhR modulation could facilitate both progenitor cell expansion and megakaryocyte and erythroid cell differentiation. Using a novel, pluripotent stem cell-based, chemically-defined, serum and feeder cell-free culture system, we show that the AhR is expressed in HPs and that, remarkably, AhR activation drives an unprecedented expansion of HPs, megakaryocyte-lineage cells, and erythroid-lineage cells. Further AhR modulation within rapidly expanding progenitor cell populations directs cell fate, with chronic AhR agonism permissive to erythroid differentiation and acute antagonism favoring megakaryocyte specification. These results highlight the development of a new Good Manufacturing Practice-compliant platform for generating virtually unlimited numbers of human HPs with which to scrutinize red blood cell and platelet development, including the assessment of the role of the AhR critical cell fate decisions during hematopoiesis.
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http://dx.doi.org/10.1182/blood-2012-11-466722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3716202PMC
July 2013

Mechanisms of environmental influence on human autoimmunity: a National Institute of Environmental Health Sciences expert panel workshop.

J Autoimmun 2012 Dec 28;39(4):272-84. Epub 2012 Jun 28.

Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, USA.

The mechanisms leading to autoimmune diseases remain largely unknown despite numerous lines of experimental inquiry and epidemiological evidence. The growing number of genome-wide association studies and the largely incomplete concordance for autoimmune diseases in monozygotic twins support the role of the environment (including infectious agents and chemicals) in the breakdown of tolerance leading to autoimmunity via numerous mechanisms. The present article reviews the major theories on the mechanisms of the environmental influence on autoimmunity by addressing the different degrees of confidence that characterize our knowledge. The theories discussed herein include (i) the role of innate immunity mediated by toll-like receptors in triggering the autoimmune adaptive response characterizing the observed pathology; (ii) changes in spleen marginal zone B cells in autoantibody production with particular focus on the B10 subpopulation; (iii) Th17 cell differentiation and T regulatory cells in the aryl hydrocarbon receptor model; (iv) self antigen changes induced by chemical and infectious agents which could break tolerance by post-translational modifications and molecular mimicry; and finally (v) epigenetic changes, particularly DNA methylation, that are induced by environmental stimuli and may contribute to autoimmunity initiation. We are convinced that these working hypotheses, in most cases supported by solid evidence, should be viewed in parallel with animal models and epidemiological observations to provide a comprehensive picture of the environmental causes of autoimmune diseases.
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http://dx.doi.org/10.1016/j.jaut.2012.05.007DOI Listing
December 2012

You AhR what you eat?

Nat Immunol 2012 Jan 19;13(2):117-9. Epub 2012 Jan 19.

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http://dx.doi.org/10.1038/ni.2213DOI Listing
January 2012