scholarly journals Immunotoxicity of Xenobiotics in Fish: A Role for the Aryl Hydrocarbon Receptor (AhR)?

2021 ◽  
Vol 22 (17) ◽  
pp. 9460
Author(s):  
Helmut Segner ◽  
Christyn Bailey ◽  
Carolina Tafalla ◽  
Jun Bo
Keyword(s):  
Immune System ◽  
Aryl Hydrocarbon Receptor ◽  
Disease Susceptibility ◽  
Immune Cell ◽  
Physiological Role ◽  
Immune Gene ◽  
Immune Systems ◽  
Aryl Hydrocarbon ◽  
The Impact

The impact of anthropogenic contaminants on the immune system of fishes is an issue of growing concern. An important xenobiotic receptor that mediates effects of chemicals, such as halogenated aromatic hydrocarbons (HAHs) and polyaromatic hydrocarbons (PAHs), is the aryl hydrocarbon receptor (AhR). Fish toxicological research has focused on the role of this receptor in xenobiotic biotransformation as well as in causing developmental, cardiac, and reproductive toxicity. However, biomedical research has unraveled an important physiological role of the AhR in the immune system, what suggests that this receptor could be involved in immunotoxic effects of environmental contaminants. The aims of the present review are to critically discuss the available knowledge on (i) the expression and possible function of the AhR in the immune systems of teleost fishes; and (ii) the impact of AhR-activating xenobiotics on the immune systems of fish at the levels of immune gene expression, immune cell proliferation and immune cell function, immune pathology, and resistance to infectious disease. The existing information indicates that the AhR is expressed in the fish immune system, but currently, we have little understanding of its physiological role. Exposure to AhR-activating contaminants results in the modulation of numerous immune structural and functional parameters of fish. Despite the diversity of fish species studied and the experimental conditions investigated, the published findings rather uniformly point to immunosuppressive actions of xenobiotic AhR ligands in fish. These effects are often associated with increased disease susceptibility. The fact that fish populations from HAH- and PAH-contaminated environments suffer immune disturbances and elevated disease susceptibility highlights that the immunotoxic effects of AhR-activating xenobiotics bear environmental relevance.

scholarly journals Toward Understanding the Role of Aryl Hydrocarbon Receptor in the Immune System: Current Progress and Future Trends

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Hamza Hanieh
Keyword(s):  
Immune System ◽  
Aryl Hydrocarbon Receptor ◽  
Immune Cells ◽  
Immune Cell ◽  
Current Knowledge ◽  
Physiological Role ◽  
Clinical Practices ◽  
Aryl Hydrocarbon ◽  
Active Research

The immune system is regulated by distinct signaling pathways that control the development and function of the immune cells. Accumulating evidence suggest that ligation of aryl hydrocarbon receptor (Ahr), an environmentally responsive transcription factor, results in multiple cross talks that are capable of modulating these pathways and their downstream responsive genes. Most of the immune cells respond to such modulation, and many inflammatory response-related genes contain multiple xenobiotic-responsive elements (XREs) boxes upstream. Active research efforts have investigated the physiological role of Ahr in inflammation and autoimmunity using different animal models. Recently formed paradigm has shown that activation of Ahr by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 3,3′-diindolylmethane (DIM) prompts the differentiation of CD4+Foxp3+regulatory T cells (Tregs) and inhibits T helper (Th)-17 suggesting that Ahr is an innovative therapeutic strategy for autoimmune inflammation. These promising findings generate a basis for future clinical practices in humans. This review addresses the current knowledge on the role of Ahr in different immune cell compartments, with a particular focus on inflammation and autoimmunity.

scholarly journals Modulation of Immune Responses by Nutritional Ligands of Aryl Hydrocarbon Receptor

2021 ◽  
Vol 12 ◽  
Author(s):  
Alba De Juan ◽  
Elodie Segura
Keyword(s):  
Immune Responses ◽  
Aryl Hydrocarbon Receptor ◽  
Immune Cell ◽  
Physiological Role ◽  
Mononuclear Phagocytes ◽  
Lymphoid Cells ◽  
Aryl Hydrocarbon ◽  
Tryptophan Catabolites ◽  
The Impact

Accumulating evidence indicates that nutrition can modulate the immune system through metabolites, either produced by host digestion or by microbiota metabolism. In this review, we focus on dietary metabolites that are agonists of the Aryl hydrocarbon Receptor (AhR). AhR is a ligand-activated transcription factor, initially characterized for its interaction with xenobiotic pollutants. Numerous studies have shown that AhR also recognizes indoles and tryptophan catabolites originating from dietary compounds and commensal bacteria. Here, we review recent work employing diet manipulation to address the impact of nutritional AhR agonists on immune responses, both locally in the intestine and at distant sites. In particular, we examine the physiological role of these metabolites in immune cell development and functions (including T lymphocytes, innate-like lymphoid cells, and mononuclear phagocytes) and their effect in inflammatory disorders.

scholarly journals Endotoxin-Induced Tryptophan Degradation along the Kynurenine Pathway: The Role of Indolamine 2,3-Dioxygenase and Aryl Hydrocarbon Receptor-Mediated Immunosuppressive Effects in Endotoxin Tolerance and Cancer and Its Implications for Immunoparalysis

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Elisa Wirthgen ◽  
Andreas Hoeflich
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Immune Escape ◽  
Endotoxin Tolerance ◽  
Kynurenine Pathway ◽  
Aryl Hydrocarbon ◽  
Tryptophan Degradation ◽  
Inflammatory Stimuli ◽  
Life Threatening ◽  
The Impact

The degradation of tryptophan (TRP) along the kynurenine pathway plays a crucial role as a neuro- and immunomodulatory mechanism in response to inflammatory stimuli, such as lipopolysaccharides (LPS). In endotoxemia or sepsis, an enhanced activation of the rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO) is associated with a higher mortality risk. It is assumed that IDO induced immunosuppressive effects provoke the development of a protracted compensatory hypoinflammatory phase up to a complete paralysis of the immune system, which is characterized by an endotoxin tolerance. However, the role of IDO activation in the development of life-threatening immunoparalysis is still poorly understood. Recent reports described the impact of inflammatory IDO activation and aryl hydrocarbon receptor- (AhR-) mediated pathways on the development of LPS tolerance and immune escape of cancer cells. These immunosuppressive mechanisms offer new insights for a better understanding of the development of cellular dysfunctions in immunoparalysis. This review provides a comprehensive update of significant biological functions of TRP metabolites along the kynurenine pathway and the complex regulation of LPS-induced IDO activation. In addition, the review focuses on the role of IDO-AhR-mediated immunosuppressive pathways in endotoxin tolerance and carcinogenesis revealing the significance of enhanced IDO activity for the establishment of life-threatening immunoparalysis in sepsis.

scholarly journals Where the Aryl Hydrocarbon Receptor Meets the microRNAs: Literature Review of the Last 10 Years

2021 ◽  
Vol 8 ◽  
Author(s):  
Geonildo Rodrigo Disner ◽  
Monica Lopes-Ferreira ◽  
Carla Lima
Keyword(s):  
Immune System ◽  
Aryl Hydrocarbon Receptor ◽  
Cancer Progression ◽  
Chemical Exposure ◽  
Epigenetic Mechanisms ◽  
Mirna Regulation ◽  
Aryl Hydrocarbon ◽  
Mutual Regulation ◽  
Polycyclic Aromatic ◽  
The Impact

The aryl hydrocarbon receptor (AhR) is an environmentally responsive ligand-activated transcription factor, identified in the ‘70s for its toxic responses to halogenated polycyclic aromatic hydrocarbons, such as dioxin. Recently, AhR has been recognized as engaged in multiple physiological processes in health and diseases, particularly in the immune system, inflammatory response, tumorigenesis, and cellular differentiation by epigenetic mechanisms involving miRNAs. However, there is still scarce information about AhR-dependent miRNA regulation and miRNA-mediated epigenetic control in pathologies and therapies. In this review, we explore the mutual regulation of AhR and miRNA over the last decade of studies since many miRNAs have dioxin response elements (DRE) in their 3’ UTR, as well as AhR might contain binding sites of miRNAs. TCDD is the most used ligand to investigate the impact of AhR activation, and the immune system is one of the most sensitive of its targets. An association between TCDD-activated AhR and epigenetic mechanisms like post-transcriptional regulation by miRNAs, DNA methylation, or histone modification has already been confirmed. Besides, several studies have shown that AhR-induced miR-212/132 cluster suppresses cancers, attenuates autoimmune diseases, and has an anti-inflammatory role in different immune responses by regulating cytokine levels and immune cells. Together the ever-expanding new AhR roles and the miRNA therapeutics are a prominent segment among biopharmaceuticals. Additionally, AhR-activated miRNAs can serve as valuable biomarkers of diseases, notably cancer progression or suppression and chemical exposure. Once AhR-dependent gene expression may hinge on the ligand, cell type, and context singularity, the reviewed outcomes might help contextualize state of the art and support new trends and emerging opportunities in the field.

The Functional Significance of Endocrine-immune Interactions in Health and Disease

2020 ◽  
Vol 21 (1) ◽  
pp. 52-65
Author(s):  
Sridhar Muthusami ◽  
Balasubramanian Vidya ◽  
Esaki M Shankar ◽  
Jamuna Vadivelu ◽  
Ilangovan Ramachandran ◽  
...  
Keyword(s):  
Immune System ◽  
Cell Differentiation ◽  
Amino Acid ◽  
Functional Role ◽  
Immune Cell ◽  
Amino Acid Derivatives ◽  
Endocrine Glands ◽  
Immune Systems ◽  
Health And Disease

Hormones are known to influence various body systems that include skeletal, cardiac, digestive, excretory, and immune systems. Emerging investigations suggest the key role played by secretions of endocrine glands in immune cell differentiation, proliferation, activation, and memory attributes of the immune system. The link between steroid hormones such as glucocorticoids and inflammation is widely known. However, the role of peptide hormones and amino acid derivatives such as growth and thyroid hormones, prolactin, dopamine, and thymopoietin in regulating the functioning of the immune system remains unclear. Here, we reviewed the findings pertinent to the functional role of hormone-immune interactions in health and disease and proposed perspective directions for translational research in the field.

scholarly journals Trajectory Shifts in Interdisciplinary Research of the Aryl Hydrocarbon Receptor—A Personal Perspective on Thymus and Skin

2021 ◽  
Vol 22 (4) ◽  
pp. 1844
Author(s):  
Charlotte Esser
Keyword(s):  
Transcription Factor ◽  
Immune System ◽  
Environmental Pollution ◽  
Aryl Hydrocarbon Receptor ◽  
Interdisciplinary Research ◽  
Adaptive Response ◽  
Personal Perspective ◽  
Aryl Hydrocarbon

Identifying historical trajectories is a useful exercise in research, as it helps clarify important, perhaps even “paradigmatic”, shifts in thinking and moving forward in science. In this review, the development of research regarding the role of the transcription factor “aryl hydrocarbon receptor” (AHR) as a mediator of the toxicity of environmental pollution towards a link between the environment and a healthy adaptive response of the immune system and the skin is discussed. From this fascinating development, the opportunities for targeting the AHR in the therapy of many diseases become clear.

scholarly journals Deletion of the Aryl Hydrocarbon Receptor-associated Protein 9 Leads to Cardiac Malformation and Embryonic Lethality

2007 ◽  
Vol 282 (49) ◽  
pp. 35924-35932 ◽  
Author(s):  
Bernice C. Lin ◽  
Ruth Sullivan ◽  
Youngsook Lee ◽  
Susan Moran ◽  
Edward Glover ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Cardiac Development ◽  
Physiological Role ◽  
Homozygous Deletion ◽  
Embryonic Lethality ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Associated Protein ◽  
Aryl Hydrocarbon

The aryl hydrocarbon receptor-associated protein 9, ARA9 (also known as XAP2 or AIP1), is a chaperone that is found in complexes with certain xenobiotic receptors, such as the aryl hydrocarbon receptor (AHR) and the peroxisome proliferator-activated receptor α (PPARα). In an effort to better understand the physiological role of ARA9 outside of its role in xenobiotic signal transduction, we generated a null allele at the Ara9 locus in mice. Mice with a homozygous deletion of this gene die at various time points throughout embryonic development. Embryonic lethality is accompanied by decreased blood flow to head and limbs, as well as a range of heart deformations, including double outlet right ventricle, ventricular-septal defects, and pericardial edema. The early cardiovascular defects observed in Ara9-null mice suggest an essential role for the ARA9 protein in cardiac development. The observation that the developmental aberrations in Ara9-null mice are distinct from those observed for disrupted alleles at Ahr or Pparα indicates that the role of ARA9 in cardiac development is independent of its interactions with its known xenobiotic receptor partners.

scholarly journals Characterizing the Role of HMG-CoA Reductase in Aryl Hydrocarbon Receptor-Mediated Liver Injury in C57BL/6 Mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Peter Dornbos ◽  
Amanda Jurgelewicz ◽  
Kelly A. Fader ◽  
Kurt Williams ◽  
Timothy R. Zacharewski ◽  
...  
Keyword(s):  
Liver Injury ◽  
Aryl Hydrocarbon Receptor ◽  
Cholesterol Biosynthesis ◽  
Competitive Inhibitor ◽  
Cholesterol Homeostasis ◽  
Hepatic Glycogen ◽  
Alcoholic Fatty Liver ◽  
Female Mice ◽  
Aryl Hydrocarbon ◽  
The Impact

Abstract The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor. The prototypical ligand of the AHR is an environmental contaminant called 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD exposure is associated with many adverse health outcomes in humans including non-alcoholic fatty liver disease (NAFLD). Previous studies suggest that AHR ligands alter cholesterol homeostasis in mice through repression of genes involved in cholesterol biosynthesis, such as Hmgcr, which encodes the rate-limiting enzyme of cholesterol biosynthesis called 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR). In this study, we sought to characterize the impact of HMGCR repression in TCDD-induced liver injury. C57BL/6 mice were exposed to TCDD in the presence or absence of simvastatin, a competitive inhibitor of HMGCR. Simvastatin exposure decreased TCDD-induced hepatic lipid accumulation in both sexes, but was most prominent in females. Simvastatin and TCDD (S + T) co-treatment increased hepatic AHR-battery gene expression and liver injury in male, but not female, mice. In addition, the S + T co-treatment led to an increase in hepatic glycogen content that coincides with heavier liver in female mice. Results from this study suggest that statins, which are amongst the most prescribed pharmaceuticals, may protect from AHR-mediated steatosis, but alter glycogen metabolism and increase the risk of TCDD-elicited liver damage in a sex-specific manner.

scholarly journals Neonatal Immune System Ontogeny: The Role of Maternal Microbiota and Associated Factors. How Might the Non-Human Primate Model Enlighten the Path?

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 584
Author(s):  
Natalia Nunez ◽  
Louis Réot ◽  
Elisabeth Menu
Keyword(s):  
Immune System ◽  
Mode Of Delivery ◽  
Microbial Colonization ◽  
Therapeutic Interventions ◽  
Primate Model ◽  
Neonatal Immune System ◽  
Gastrointestinal Colonization ◽  
The Impact ◽  
Human Primate

Interactions between the immune system and the microbiome play a crucial role on the human health. These interactions start in the prenatal period and are critical for the maturation of the immune system in newborns and infants. Several factors influence the composition of the infant’s microbiota and subsequently the development of the immune system. They include maternal infection, antibiotic treatment, environmental exposure, mode of delivery, breastfeeding, and food introduction. In this review, we focus on the ontogeny of the immune system and its association to microbial colonization from conception to food diversification. In this context, we give an overview of the mother–fetus interactions during pregnancy, the impact of the time of birth and the mode of delivery, the neonate gastrointestinal colonization and the role of breastfeeding, weaning, and food diversification. We further review the impact of the vaccination on the infant’s microbiota and the reciprocal case. Finally, we discuss several potential therapeutic interventions that might help to improve the newborn and infant’s health and their responses to vaccination. Throughout the review, we underline the main scientific questions that are left to be answered and how the non-human primate model could help enlighten the path.

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