The Aryl Hydrocarbon Receptor Is Required for Optimal Resistance to <i>Listeria monocytogenes</i> Infection in Mice

Shi, Lewis Zhichang; Faith, Nancy G.; Nakayama, Yasuya; Suresh, M.; Steinberg, Howard; Czuprynski, Charles J.

doi:10.4049/jimmunol.179.10.6952

Cited by 75 publications

(61 citation statements)

References 55 publications

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“…Memory response against a protein Ag was reported (8). However, they are more susceptible to infections with Helicobacter hepaticus, an opportunistic infection indicating immunodeficiency (50,51), and to L.monocytogenes (52). The underlying cause may be specific defects in the immune system or other general damages resulting from AhR deficiency.…”

Section: Discussionmentioning

confidence: 99%

Langerhans Cell Maturation and Contact Hypersensitivity Are Impaired in Aryl Hydrocarbon Receptor-Null Mice

Jux

Kadow

Esser

2009

The Journal of Immunology

127

115

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Langerhans cells (LC) are professional APCs of the epidermis. Recently, it was suggested that they are tolerogenic and control adverse immune reactions, including against low molecular mass chemicals. The aryl hydrocarbon receptor (AhR), a ligandactivated transcription factor, is involved in low molecular mass chemical metabolism and cell differentiation. Growing evidence suggests a role for the AhR in the immune system, for example, by influencing dendritic cell and T cell differentiation. We found that the AhR and its repressor AhRR are expressed in LC of C57BL/6 mice. LC, unexpectedly, did not respond to a strong AhR agonist with induction of transcripts of xenobiotic metabolizing enzymes. To test for a physiological role of the AhR in LC, we investigated how AhR deficiency affects LC. We found that AhR-deficient LC were impaired in maturation; they remained smaller and less granular, did not up-regulate expression of costimulatory molecules CD40, CD80, and CD24a during in vitro maturation, and their phagocytic capacity was higher. Interestingly, the mRNA expression of tolerogenic Ido was severely decreased in AhR-deficient LC, and enzyme activity could not be induced in AhR-deficient bone marrow-derived dendritic cells. GM-CSF, needed for LC maturation, was secreted in significantly lower amounts by AhR-deficient epidermal cells. Congruent with this impaired maturity and capacity to mature, mice mounted significantly weaker contact hypersensitivity against FITC. Our data suggest that the AhR is involved in LC maturation, both cell autonomously and through bystander cells. At the same time, the AhR might be part of the risk strategy of LC against unwanted immune activation by potential skin allergens.

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Section: Discussionmentioning

confidence: 99%

Langerhans Cell Maturation and Contact Hypersensitivity Are Impaired in Aryl Hydrocarbon Receptor-Null Mice

Jux

Kadow

Esser

2009

The Journal of Immunology

127

115

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“…In fact, the Ahr(Ϫ/Ϫ) knockout mouse displays patent ductus venosus and other arteriovenous-shunt problems (Lahvis et al, 2005), along with immune dysregulation (FernandezSalguero et al, 1995), and increased susceptibility to infection (Shi et al, 2007)-probably caused also by perturbation of eicosanoid function. Indeed, six different prostaglandins (albeit at relatively high concentrations) have been shown to activate the AHR and induce the CYP1 enzymes (Seidel et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Phenotype of theCyp1a1/1a2/1b1(-/-) Triple-Knockout Mouse

et al. 2008

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Crossing the Cyp1a1/1a2(Ϫ/Ϫ) double-knockout mouse with the Cyp1b1(Ϫ/Ϫ) single-knockout mouse, we generated the Cyp1a1/1a2/1b1(Ϫ/Ϫ) triple-knockout mouse. In this tripleknockout mouse, statistically significant phenotypes (with incomplete penetrance) included slower weight gain and greater risk of embryolethality before gestational day 11, hydrocephalus, hermaphroditism, and cystic ovaries. Oral benzo[a]pyrene (BaP) daily for 18 days in the Cyp1a1/1a2(Ϫ/Ϫ) produced the same degree of marked immunosuppression as seen in the Cyp1a1(Ϫ/Ϫ) mouse; we believe this reflects the absence of intestinal CYP1A1. Oral BaP-treated Cyp1a1/1a2/1b1(Ϫ/Ϫ) mice showed the same "rescued" response as that seen in the Cyp1a1/1b1(Ϫ/Ϫ) mouse; we believe this reflects the absence of CYP1B1 in immune tissues. Urinary metabolite profiles were dramatically different between untreated triple-knockout and wild-type; principal components analysis showed that the shifts in urinary metabolite patterns in oral BaP-treated triple-knockout and wild-type mice were also strikingly different. Liver microarray cDNA differential expression (comparing triple-knockout with wild-type) revealed at least 89 genes up-and 62 genes down-regulated (P-value <0.00086). Gene Ontology "classes of genes" most perturbed in the untreated triple-knockout (compared with wild-type) include lipid, steroid, and cholesterol biosynthesis and metabolism; nucleosome and chromatin assembly; carboxylic and organic acid metabolism; metal-ion binding; and ion homeostasis. In the triple-knockout compared with the wild-type mice, response to zymosan-induced peritonitis was strikingly exaggerated, which may well reflect downregulation of Socs2 expression. If a single common molecular pathway is responsible for all of these phenotypes, we suggest that functional effects of the loss of all three Cyp1 genes could be explained by perturbations in CYP1-mediated eicosanoid production, catabolism and activities.

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“…The major immune mechanisms controlled by AhR are related to the activation and differentiation of specific T cell subsets (T regulatory [Treg] and Th17) and antigenpresenting cells (3). In the context of immunity to infections, it was demonstrated that AhR is an essential protein for murine resistance to Listeria monocytogenes (7) and toxoplasmosis (8).…”

mentioning

confidence: 99%

The Aryl Hydrocarbon Receptor Modulates Production of Cytokines and Reactive Oxygen Species and Development of Myocarditis during Trypanosoma cruzi Infection

et al. 2016

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eThe aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in controlling several aspects of immune responses, including the activation and differentiation of specific T cell subsets and antigen-presenting cells, thought to be relevant in the context of experimental Trypanosoma cruzi infection. The relevance of AhR for the outcome of T. cruzi infection is not known and was investigated here. We infected wild-type (WT) mice and AhR knockout (AhR KO) mice with T. cruzi (Y strain) and determined levels of parasitemia, myocardial inflammation and fibrosis, expression of AhR/cytokines/suppressor of cytokine signaling (SOCS) (spleen/heart), and production of nitric oxide (NO), reactive oxygen species (ROS), and peroxynitrite (ONOO ؊ ) (spleen). AhR expression was increased in the heart of infected WT mice. Infected AhR KO mice displayed significantly reduced parasitemia, inflammation, and fibrosis of the myocardium. This was associated with an anticipated increased immune response characterized by increased levels of inflammatory cytokines and reduced expression of SOCS2 and SOCS3 in the heart. In vitro, AhR deficiency caused impairment in parasite replication and decreased levels of ROS production. In conclusion, AhR influences the development of murine Chagas disease by modulating ROS production and regulating the expression of key physiological regulators of inflammation, SOCS1 to -3, associated with the production of cytokines during experimental T. cruzi infection. The aryl hydrocarbon receptor (AhR) was originally described as a ligand-dependent transcription factor for exogenous ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) capable of activating the aryl hydrocarbon hydroxylase (1, 2). In humans and mice, AhR recognizes several endogenous ligands, such as 6-formylindolo[3,2-b]carbazole (FICZ), kynurenines, indoles (3, 4), and lipoxins (LX) (5). The activation of the AhR signaling pathway controls the genomic expression of diverse target genes, leading to different physiological outcomes (6). More recently, it has been recognized that AhR is involved in the regulation of several immune processes. The major immune mechanisms controlled by AhR are related to the activation and differentiation of specific T cell subsets (T regulatory [Treg] and Th17) and antigenpresenting cells (3). In the context of immunity to infections, it was demonstrated that AhR is an essential protein for murine resistance to Listeria monocytogenes (7) and toxoplasmosis (8).More recently, we found that it was an important factor in controlling parasitemia and inflammation during experimental cerebral malaria (9). Additionally, it is associated with antiviral immunity (10) and is a negative regulator of inflammatory cytokines in response to Leishmania major experimental infection (11). Taken together, the results of these studies strongly suggest that AhR function during immune responses to infections is complex and likely pathogen specific.Trypanosoma cruzi is a flagellated protozoan parasite that...

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The Aryl Hydrocarbon Receptor Is Required for Optimal Resistance to Listeria monocytogenes Infection in Mice

Cited by 75 publications

References 55 publications

Langerhans Cell Maturation and Contact Hypersensitivity Are Impaired in Aryl Hydrocarbon Receptor-Null Mice

Langerhans Cell Maturation and Contact Hypersensitivity Are Impaired in Aryl Hydrocarbon Receptor-Null Mice

Phenotype of theCyp1a1/1a2/1b1(-/-) Triple-Knockout Mouse

The Aryl Hydrocarbon Receptor Modulates Production of Cytokines and Reactive Oxygen Species and Development of Myocarditis during Trypanosoma cruzi Infection

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