Tryptophan Metabolites at the Crossroad of Immune-Cell Interaction via the Aryl Hydrocarbon Receptor: Implications for Tumor Immunotherapy

The Aryl hydrocarbon receptor (AhR) is a critical regulator of both innate and adaptive immune responses, with potent immunomodulatory effects that makes this receptor an attractive molecular target for novel therapeutics. Accumulating evidence indicates that diverse—both host’s and microbial—tryptophan metabolites profoundly regulate the immune system in the host via AhR, promoting either tolerance or immunity, largely as a function of the qualitative and quantitative nature of the metabolites being contributed by either source. Additional findings indicate that host and microbiota-derived tryptophan metabolic pathways can influence the outcome of immune responses to tumors. Here, we review recent studies on the role and modalities of AhR activation by various ligands, derived from either host-cell or microbial-cell tryptophan metabolic pathways, in the regulation of immune responses. Moreover, we highlight potential implications of those ligands and pathways in tumor immunotherapy, with particular relevance to checkpoint-blockade immune intervention strategies.

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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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The Aryl Hydrocarbon Receptor as a Modulator of Anti-viral Immunity

Frontiers in Immunology ◽

10.3389/fimmu.2021.624293 ◽

2021 ◽

Vol 12 ◽

Author(s):

Maria Florencia Torti ◽

Federico Giovannoni ◽

Francisco Javier Quintana ◽

Cybele Carina García

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Target Genes ◽

Environmental Pollutants ◽

Adaptive Immune Response ◽

Viral Immunity ◽

Adaptive Immune ◽

Aryl Hydrocarbon ◽

Wide Range ◽

Tryptophan Metabolites ◽

Exogenous Origin

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, which interacts with a wide range of organic molecules of endogenous and exogenous origin, including environmental pollutants, tryptophan metabolites, and microbial metabolites. The activation of AHR by these agonists drives its translocation into the nucleus where it controls the expression of a large number of target genes that include the AHR repressor (AHRR), detoxifying monooxygenases (CYP1A1 and CYP1B1), and cytokines. Recent advances reveal that AHR signaling modulates aspects of the intrinsic, innate and adaptive immune response to diverse microorganisms. This review will focus on the increasing evidence supporting a role for AHR as a modulator of the host response to viral infection.

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The aryl hydrocarbon receptor in liver inflammation

Seminars in Immunopathology ◽

10.1007/s00281-021-00867-8 ◽

2021 ◽

Author(s):

Antonella Carambia ◽

Fenja Amrei Schuran

Keyword(s):

Liver Disease ◽

Immune Responses ◽

Aryl Hydrocarbon Receptor ◽

Current Knowledge ◽

Regulatory Factor ◽

Potential Therapeutic Target ◽

Adaptive Immune ◽

Aryl Hydrocarbon ◽

Healthy Liver

AbstractThe aryl hydrocarbon receptor (AHR) is a ubiquitously expressed ligand-activated transcription factor with multifaceted physiological functions. In the immune system, AHR has been unequivocally identified as a key regulatory factor that can integrate environmental, dietary, or microbial signals into innate and adaptive immune responses. Correspondingly, AHR activity seems to be most important at barrier organs, such as the gut, skin, and lung. The liver is likewise prominently exposed to gut-derived dietary or microbial AHR ligands and, moreover, generates plenty of AHR ligands itself. Yet, surprisingly little is known about the role of AHR in the regulation of hepatic immune responses, which are normally biased towards tolerance, preventing harmful inflammation in response to innocuous stimuli. In this review, we summarize the current knowledge about the role of AHR in hepatic immune responses in the healthy liver as well as in inflammatory liver disease. Moreover, we discuss AHR as a potential therapeutic target in hepatic disorders, including autoimmune liver disease, liver fibrosis, and liver cancer.

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The complement anaphylatoxin C3a is critical in generating both innate and adaptive immune responses to Listeria monocytogenes due to its indispensible role in immune cell survival

Immunobiology ◽

10.1016/j.imbio.2012.08.230 ◽

2012 ◽

Vol 217 (11) ◽

pp. 1209 ◽

Cited By ~ 1

Author(s):

Stacey L. Mueller-Ortiz ◽

John E. Morales ◽

Amanda Clark ◽

Rick A. Wetsel

Keyword(s):

Listeria Monocytogenes ◽

Immune Responses ◽

Cell Survival ◽

Immune Cell ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Anaphylatoxin C3a

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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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A functional spleen contributes to afucosylated IgG in humans

Scientific Reports ◽

10.1038/s41598-021-03196-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Iwona Wojcik ◽

David E. Schmidt ◽

Lisa A. de Neef ◽

Minke A. E. Rab ◽

Bob Meek ◽

...

Keyword(s):

Immune Responses ◽

Viral Infections ◽

Immune Cell ◽

Lymphoid Organ ◽

Immune Effector ◽

Adaptive Immune ◽

Wide Range ◽

Humoral Responses ◽

First Time

AbstractAs a lymphoid organ, the spleen hosts a wide range of immune cell populations, which not only remove blood-borne antigens, but also generate and regulate antigen-specific immune responses. In particular, the splenic microenvironment has been demonstrated to play a prominent role in adaptive immune responses to enveloped viral infections and alloantigens. During both types of immunizations, antigen-specific immunoglobulins G (IgGs) have been characterized by the reduced amount of fucose present on N-linked glycans of the fragment crystallizable (Fc) region. These glycans are essential for mediating the induction of immune effector functions. Therefore, we hypothesized that a spleen may modulate humoral responses and serve as a preferential site for afucosylated IgG responses, which potentially play a role in immune thrombocytopenia (ITP) pathogenesis. To determine the role of the spleen in IgG-Fc glycosylation, we performed IgG subclass-specific liquid chromatography–mass spectrometry (LC–MS) analysis of Fc glycosylation in a large cohort of individuals splenectomized due to trauma, due to ITP, or spherocytosis. IgG-Fc fucosylation was consistently increased after splenectomy, while no effects for IgG-Fc galactosylation and sialylation were observed. An increase in IgG1- and IgG2/3-Fc fucosylation level upon splenectomy has been reported here for the first time, suggesting that immune responses occurring in the spleen may be particularly prone to generate afucosylated IgG responses. Surprisingly, the level of total IgG-Fc fucosylation was decreased in ITP patients compared to healthy controls. Overall, our results suggest a yet unrecognized role of the spleen in either the induction or maintenance of afucosylated IgG responses by B cells.

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Tryptophan Metabolism Activates Aryl Hydrocarbon Receptor-Mediated Pathway To Promote HIV-1 Infection and Reactivation

mBio ◽

10.1128/mbio.02591-19 ◽

2019 ◽

Vol 10 (6) ◽

Author(s):

Yan-Heng Zhou ◽

Li Sun ◽

Jun Chen ◽

Wei-Wei Sun ◽

Li Ma ◽

...

Keyword(s):

Transcription Factor ◽

Aryl Hydrocarbon Receptor ◽

Metabolic Pathways ◽

Nuclear Translocation ◽

Underlying Mechanism ◽

Hiv Pathogenesis ◽

Downstream Target ◽

Potential Target ◽

Aryl Hydrocarbon ◽

Hiv 1

ABSTRACT Multiple cellular metabolic pathways are altered by HIV-1 infection, with an impact on immune activation, inflammation, and acquisition of non-AIDS comorbid diseases. The dysfunction of tryptophan (Trp) metabolism has been observed clinically in association with accelerated HIV-1 pathogenesis, but the underlying mechanism remains unknown. In this study, we demonstrated that the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, is activated by Trp metabolites to promote HIV-1 infection and reactivation. AHR directly binds to the HIV-1 5′ long terminal repeat (5′-LTR) at the molecular level to activate viral transcription and infection, and AHR activation by Trp metabolites increases its nuclear translocation and association with the HIV 5′-LTR; moreover, the binding of AHR with HIV-1 Tat facilitates the recruitment of positive transcription factors to viral promoters. These findings not only elucidate a previously unappreciated mechanism through which cellular Trp metabolites affect HIV pathogenesis but also suggest that a downstream target AHR may be a potential target for modulating HIV-1 infection. IMPORTANCE Cellular metabolic pathways that are altered by HIV-1 infection may accelerate disease progression. Dysfunction in tryptophan (Trp) metabolism has been observed clinically in association with accelerated HIV-1 pathogenesis, but the mechanism responsible was not known. This study demonstrates that Trp metabolites augment the activation of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, to promote HIV-1 infection and transcription. These findings not only elucidate a previously unappreciated mechanism through which cellular Trp metabolites affect HIV pathogenesis but also suggest that a downstream target AHR may be a potential target for modulating HIV-1 infection.

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Microbiota tryptophan metabolism induces aryl hydrocarbon receptor activation and improves alcohol-induced liver injury

Gut ◽

10.1136/gutjnl-2020-321565 ◽

2020 ◽

pp. gutjnl-2020-321565 ◽

Cited By ~ 1

Author(s):

Laura Wrzosek ◽

Dragos Ciocan ◽

Cindy Hugot ◽

Madeleine Spatz ◽

Margot Dupeux ◽

...

Keyword(s):

Liver Disease ◽

Liver Injury ◽

Aryl Hydrocarbon Receptor ◽

Intestinal Microbiota ◽

Alcoholic Liver Disease ◽

Receptor Activation ◽

Liver Lesions ◽

Knock Out ◽

Aryl Hydrocarbon ◽

Tryptophan Metabolites

ObjectiveChronic alcohol consumption is an important cause of liver-related deaths. Specific intestinal microbiota profiles are associated with susceptibility or resistance to alcoholic liver disease in both mice and humans. We aimed to identify the mechanisms by which targeting intestinal microbiota can improve alcohol-induced liver lesions.DesignWe used human associated mice, a mouse model of alcoholic liver disease transplanted with the intestinal microbiota of alcoholic patients and used the prebiotic, pectin, to modulate the intestinal microbiota. Based on metabolomic analyses, we focused on microbiota tryptophan metabolites, which are ligands of the aryl hydrocarbon receptor (AhR). Involvement of the AhR pathway was assessed using both a pharmacological approach and AhR-deficient mice.ResultsPectin treatment modified the microbiome and metabolome in human microbiota-associated alcohol-fed mice, leading to a specific faecal signature. High production of bacterial tryptophan metabolites was associated with an improvement of liver injury. The AhR agonist Ficz (6-formylindolo (3,2-b) carbazole) reduced liver lesions, similarly to prebiotic treatment. Conversely, inactivation of the ahr gene in alcohol-fed AhR knock-out mice abrogated the beneficial effects of the prebiotic. Importantly, patients with severe alcoholic hepatitis have low levels of bacterial tryptophan derivatives that are AhR agonists.ConclusionsImprovement of alcoholic liver disease by targeting the intestinal microbiota involves the AhR pathway, which should be considered as a new therapeutic target.

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