The aryl hydrocarbon receptor as a target of environmental stressors – Implications for pollution mediated stress and inflammatory responses

Aryl hydrocarbon receptor (AhR), an important nuclear receptor, regulates the cellular response to environmental stressors. It is well known for its critical functions in toxicology, but is currently considered an essential regulator of diseases, with specific modulatory effects on immune, antimicrobial and inflammatory responses. The present chapter discusses AhR’s function and mechanism in the immune response against microbial infections.

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A Protective Role of Aryl Hydrocarbon Receptor Repressor in Inflammation and Tumor Growth

Cancers ◽

10.3390/cancers11050589 ◽

2019 ◽

Vol 11 (5) ◽

pp. 589 ◽

Cited By ~ 4

Author(s):

Christoph F. A. Vogel ◽

Yasuhiro Ishihara ◽

Claire E. Campbell ◽

Sarah Y. Kado ◽

Aimy Nguyen-Chi ◽

...

Keyword(s):

Tumor Growth ◽

Aryl Hydrocarbon Receptor ◽

Inflammatory Responses ◽

Environmental Pollutants ◽

Protective Role ◽

Potential Therapeutic Target ◽

Embryonic Fibroblasts ◽

Aryl Hydrocarbon ◽

Enhancer Binding Protein

The aryl hydrocarbon receptor (AhR) is known for mediating the toxicity of environmental pollutants such as dioxins and numerous dioxin-like compounds, and is associated with the promotion of various malignancies, including lymphoma. The aryl hydrocarbon receptor repressor (AhRR), a ligand-independent, transcriptionally inactive AhR-like protein is known to repress AhR signaling through its ability to compete with the AhR for dimerization with the AhR nuclear translocator (ARNT). While AhRR effectively blocks AhR signaling, several aspects of the mechanism of AhRR’s functions are poorly understood, including suppression of inflammatory responses and its putative role as a tumor suppressor. In a transgenic mouse that overexpresses AhRR (AhRR Tg) we discovered that these mice suppress 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)- and inflammation-induced tumor growth after subcutaneous challenge of EL4 lymphoma cells. Using mouse embryonic fibroblasts (MEF) we found that AhRR overexpression suppresses the AhR-mediated anti-apoptotic response. The AhRR-mediated inhibition of apoptotic resistance was associated with a suppressed expression of interleukin (IL)-1β and cyclooxygenase (COX)-2, which was dependent on activation of protein kinase A (PKA) and the CAAT-enhancer-binding protein beta (C/EBPβ). These results provide mechanistic insights into the role of the AhRR to suppress inflammation and highlight the AhRR as a potential therapeutic target to suppress tumor growth.

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The Role of the Aryl Hydrocarbon Receptor (AHR) in Immune and Inflammatory Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms19123851 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3851 ◽

Cited By ~ 38

Author(s):

Drew Neavin ◽

Duan Liu ◽

Balmiki Ray ◽

Richard Weinshilboum

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Nuclear Receptor ◽

Binding Sites ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Dependent Manner ◽

Nucleotide Polymorphisms ◽

Aryl Hydrocarbon ◽

Inflammatory Processes ◽

Targeted Gene Expression

The aryl hydrocarbon receptor (AHR) is a nuclear receptor that modulates the response to environmental stimuli. It was recognized historically for its role in toxicology but, in recent decades, it has been increasingly recognized as an important modulator of disease—especially for its role in modulating immune and inflammatory responses. AHR has been implicated in many diseases that are driven by immune/inflammatory processes, including major depressive disorder, multiple sclerosis, rheumatoid arthritis, asthma, and allergic responses, among others. The mechanisms by which AHR has been suggested to impact immune/inflammatory diseases include targeted gene expression and altered immune differentiation. It has been suggested that single nucleotide polymorphisms (SNPs) that are near AHR-regulated genes may contribute to AHR-dependent disease mechanisms/pathways. Further, we have found that SNPs that are outside of nuclear receptor binding sites (i.e., outside of AHR response elements (AHREs)) may contribute to AHR-dependent gene regulation in a SNP- and ligand-dependent manner. This review will discuss the evidence and mechanisms of AHR contributions to immune/inflammatory diseases and will consider the possibility that SNPs that are outside of AHR binding sites might contribute to AHR ligand-dependent inter-individual variation in disease pathophysiology and response to pharmacotherapeutics.

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Activation of the aryl hydrocarbon receptor increases pulmonary neutrophilia and diminishes host resistance to influenza A virus

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00318.2004 ◽

2005 ◽

Vol 289 (1) ◽

pp. L111-L124 ◽

Cited By ~ 58

Author(s):

Sabine Teske ◽

Andrea A. Bohn ◽

Jean F. Regal ◽

Joshua J. Neumiller ◽

B. Paige Lawrence

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Influenza A Virus ◽

Influenza A ◽

Viral Infections ◽

Inflammatory Responses ◽

Neutrophil Function ◽

Aryl Hydrocarbon ◽

Potent Agonist

Unlike their role in bacterial infection, less is known about the role of neutrophils during pulmonary viral infection. Exposure to pollutant 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD, dioxin) results in excess neutrophils in the lungs of mice infected with influenza A virus. TCDD is the most potent agonist for the aryl hydrocarbon receptor (AhR), and exposure to AhR ligands has been correlated with exacerbated inflammatory lung diseases. However, knowledge of the effects of AhR agonists on neutrophils is limited. Likewise, the factors regulating neutrophil responses during respiratory viral infections are not well characterized. To address these knowledge gaps, we determined the in vivo levels of KC, MIP-1α, MIP-2, LIX, IL-6, and C5a in infected mouse lungs. Our data show that these neutrophil chemoattractants are generally produced transiently in the lung within 12–24 h of infection. We also report that expression of CD11a, CD11b, CD49d, CD31, and CD38 is increased on pulmonary neutrophils in response to influenza virus. Using AhR-deficient mice, we demonstrate that excess neutrophilia in the lung is mediated by activation of the AhR and that this enhanced neutrophilia correlates directly with decreased survival in TCDD-exposed mice. Although AhR activation results in more neutrophils in the lungs, we show that this is not mediated by deregulation in levels of common neutrophil chemoattractants, expression of adhesion molecules on pulmonary neutrophils, or delayed death of neutrophils. Likewise, exposure to TCDD did not enhance pulmonary neutrophil function. This study provides an important first step in elucidating the mechanisms by which AhR agonists exacerbate pulmonary inflammatory responses.

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Allelic variants of the aryl hydrocarbon receptor differentially influence UVB-mediated skin inflammatory responses in SKH1 mice

Toxicology ◽

10.1016/j.tox.2017.11.020 ◽

2018 ◽

Vol 394 ◽

pp. 27-34 ◽

Cited By ~ 4

Author(s):

Kayla J. Smith ◽

Iain A. Murray ◽

Jacob A. Boyer ◽

Gary H. Perdew

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Inflammatory Responses ◽

Allelic Variants ◽

Aryl Hydrocarbon

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Aryl hydrocarbon receptor regulates lipopolysaccharide-induced inflammatory responses

Cytokine ◽

10.1016/j.cyto.2009.07.461 ◽

2009 ◽

Vol 48 (1-2) ◽

pp. 109-110

Author(s):

Akihiro Kimura ◽

Tetsuji Naka ◽

Taisuke Nakahama ◽

Ichino Chinen ◽

Kazuya Masuda ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Inflammatory Responses ◽

Aryl Hydrocarbon

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Aryl hydrocarbon receptor (AHR) functions in infectious and sterile inflammation and NAD+-dependent metabolic adaptation

Archives of Toxicology ◽

10.1007/s00204-021-03134-9 ◽

2021 ◽

Author(s):

Karl Walter Bock

Keyword(s):

Energy Metabolism ◽

Aryl Hydrocarbon Receptor ◽

Stress Responses ◽

Inflammatory Responses ◽

Sterile Inflammation ◽

Metabolic Adaptation ◽

Sensitive Species ◽

Nonalcoholic Fatty Liver ◽

Aryl Hydrocarbon ◽

Dioxin Toxicity

AbstractAryl hydrocarbon receptor (AHR) research has shifted from exploring dioxin toxicity to elucidation of various physiologic AHR functions. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to exert cellular stress-mediated sterile inflammatory responses in exposed human tissues but may be lethal in sensitive species. Inflammation can be thought of as the extreme end of a spectrum ranging from homeostasis to stress responses (sterile inflammation) and to defense against infection (infectious inflammation). Defense against bacterial infection by generation of reactive oxygen species has to be strictly controlled and may use up a considerable amount of energy. NAD+-mediated energy metabolism adapts to various inflammatory responses. As examples, the present commentary tries to integrate responses of AHR and NAD+-consuming enzymes (PARP7/TiPARP, CD38 and sirtuins) into infectious and stress-induced inflammatory responses, the latter exemplified by nonalcoholic fatty liver disease (NAFLD). TCDD toxicity models in sensitive species provide hints to molecular AHR targets of energy metabolism including gluconeogenesis and glycolysis. AHR research remains challenging and promising.

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Lipopolysaccharide-Enhanced Responses against Aryl Hydrocarbon Receptor in FcgRIIb-Deficient Macrophages, a Profound Impact of an Environmental Toxin on a Lupus-Like Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms22084199 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4199

Author(s):

Kanyarat Udompornpitak ◽

Thansita Bhunyakarnjanarat ◽

Awirut Charoensappakit ◽

Cong Phi Dang ◽

Wilasinee Saisorn ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Inflammatory Responses ◽

Macrophage Polarization ◽

Environmental Pollutants ◽

Annexin V ◽

Aryl Hydrocarbon ◽

Gamma Receptor ◽

M1 Macrophage ◽

Environmental Toxin ◽

Pre Treatment

Fc gamma receptor IIb (FcgRIIb) is the only inhibitory-FcgR in the FcgR family, and FcgRIIb-deficient (FcgRIIb−/−) mice develop a lupus-like condition with hyper-responsiveness against several stimulations. The activation of aryl hydrocarbon receptor (Ahr), a cellular environmental sensor, might aggravate activity of the lupus-like condition. As such, 1,4-chrysenequinone (1,4-CQ), an Ahr-activator, alone did not induce supernatant cytokines from macrophages, while the 24 h pre-treatment by lipopolysaccharide (LPS), a representative inflammatory activator, prior to 1,4-CQ activation (LPS/1,4-CQ) predominantly induced macrophage pro-inflammatory responses. Additionally, the responses from FcgRIIb−/− macrophages were more prominent than wild-type (WT) cells as determined by (i) supernatant cytokines (TNF-α, IL-6, and IL-10), (ii) expression of the inflammation associated genes (NF-κB, aryl hydrocarbon receptor, iNOS, IL-1β and activating-FcgRIV) and cell-surface CD-86 (a biomarker of M1 macrophage polarization), and (iii) cell apoptosis (Annexin V), with the lower inhibitory-FcgRIIb expression. Moreover, 8-week-administration of 1,4-CQ in 8 week old FcgRIIb−/− mice, a genetic-prone lupus-like model, enhanced lupus characteristics as indicated by anti-dsDNA, serum creatinine, proteinuria, endotoxemia, gut-leakage (FITC-dextran), and glomerular immunoglobulin deposition. In conclusion, an Ahr activation worsened the disease severity in FcgRIIb−/− mice possibly through the enhanced inflammatory responses. The deficiency of inhibitory-FcgRIIb in these mice, at least in part, prominently enhanced the pro-inflammatory responses. Our data suggest that patients with lupus might be more vulnerable to environmental pollutants.

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Aryl hydrocarbon receptor agonist, leflunomide, protects the ischemic-reperfused kidney: role of Tregs and stem cells

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00315.2012 ◽

2012 ◽

Vol 303 (11) ◽

pp. R1136-R1146 ◽

Cited By ~ 22

Author(s):

Babak Baban ◽

Jun Yao Liu ◽

Mahmood S. Mozaffari

Keyword(s):

Stem Cells ◽

Aryl Hydrocarbon Receptor ◽

Peripheral Blood ◽

Inflammatory Responses ◽

Left Kidney ◽

Hematopoietic Stem ◽

Aryl Hydrocarbon ◽

Aryl Hydrocarbon Receptor Agonist ◽

Stems Cells ◽

The Right

The aryl hydrocarbon receptor (AHR) has emerged as a major modulator of inflammatory processes. We tested the hypothesis that AHR activation protects the ischemic-reperfused kidney in association with the suppression of the inflammatory response. Accordingly, male mice were treated with the nondioxin AHR agonist, leflunomide (40 mg/kg ip); vehicle-treated animals served as controls. Thereafter, the right kidney was subjected to an ischemia (45 min)-reperfusion (4 h) insult, while the left kidney served as a sham control. Renal cells prepared from ischemic-reperfused kidneys of leflunomide-treated mice displayed preservation of mitochondrial membrane potential (Ψm) and decreased apoptosis and necrosis compared with vehicle-treated ischemic-reperfused kidneys. Leflunomide treatment increased regulatory T cells (Tregs; forkhead box P3+) and IL-10-positive cells but reduced IL-17- and IL-23-expressing cells in both the peripheral blood and kidney cells, indicative of down-regulation of inflammatory responses. Leflunomide treatment also increased mobilization of stems cells subsets (i.e., mesenchymal and hematopoietic stem cells and endothelial progenitor cells) in the peripheral blood and promoted their recruitment into the ischemic-reperfused kidney. Collectively, the results indicate that AHR stimulation may represent a novel renoprotective mechanism likely involving mobilization and recruitment of Tregs and stem cells into the damaged kidney.

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5-HT2Bserotonin receptor agonist BW723C86 shapes the macrophage gene profile via AhR and impairs monocyte-to-osteoclast differentiation

10.1101/587709 ◽

2019 ◽

Author(s):

Concha Nieto ◽

Ignacio Rayo ◽

Mateo de las Casas-Engel ◽

Elena Izquierdo ◽

Bárbara Alonso ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Selective Serotonin Reuptake Inhibitors ◽

Inflammatory Responses ◽

Osteoclast Differentiation ◽

Human Macrophage ◽

List Type ◽

Human Macrophages ◽

Aryl Hydrocarbon ◽

Anti Inflammatory ◽

Independent Effects

ABSTRACTPeripheral serotonin (5-HT) exacerbates or limits inflammatory pathologies through interaction with seven types of 5-HT receptors (5-HT1-7). As central regulators of inflammation, macrophages are critical targets of 5-HT, which promotes their anti-inflammatory and pro-fibrotic polarization primarily via the 5-HT7-Protein Kinase A (PKA) axis. However, anti-inflammatory human macrophages are also characterized by the expression of 5-HT2B, an off-target of anesthetics, anti-parkinsonian drugs and Selective Serotonin Reuptake Inhibitors (SSRI) that contributes to 5-HT-mediated pathologies. Since 5-HT2Bprevents mononuclear phagocyte degeneration in amyotrophic lateral sclerosis and modulates motility of murine microglial processes, we sought to determine the functional and transcriptional consequences of 5-HT2Bactivation in human macrophages. Ligation of 5-HT2Bby the 5-HT2B-specific agonist BW723C86, which exhibits antidepressant- and anxiolytic-like effects in animal models, significantly modified the cytokine profile and the transcriptional signature in macrophages. Importantly, 5-HT2Bagonist-induced transcriptional changes were partly mediated through activation of the Aryl hydrocarbon Receptor (AhR), a ligand-dependent transcription factor that regulates immune responses and the biological responses to xenobiotics. Besides, BW723C86 triggered transcriptional effects that could not be abrogated by 5-HT2Bantagonists and impaired monocyte-to-osteoclast differentiation by affecting the expression of negative (IRF8) and positive (PRDM1) regulators of osteoclastogenesis. Therefore, our results demonstrate the existence of a functional 5-HT2B-AhR axis in human macrophages and indicate that the commonly used 5-HT2Bagonist BW723C86 exhibits 5-HT2B-independent effects. The 5-HT2B-AhR link extends the range of signaling pathways initiated upon 5-HT receptor engagement and identifies a point of convergence for endogenous and exogenous agents with ability to modulate inflammatory responses.KEY POINTS-The serotonin receptor 5-HT2Bmodifies the human macrophage transcriptome through activation of the Aryl Hydrocarbon Receptor.-BW723C86, an agonist used for 5-HT2Bactivationin vivo, exerts 5-HT2B-independent effects and limits monocyte osteoclastogenic potential.

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