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

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22179460 ◽

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.

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Modulation of Immune Responses by Nutritional Ligands of Aryl Hydrocarbon Receptor

Frontiers in Immunology ◽

10.3389/fimmu.2021.645168 ◽

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.

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

Scientific Reports ◽

10.1038/s41598-019-52001-2 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

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.

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