Aryl hydrocarbon receptor protects against bacterial infection by promoting macrophage survival and reactive oxygen species production

Kimura, Akihiro; Abe, Hiromi; Tsuruta, Sanae; Chiba, Sayuri; Fujii‐Kuriyama, Yoshiaki; Sekiya, Takashi; Morita, Rimpei; Yoshimura, Akihiko

doi:10.1093/intimm/dxt067

Cited by 58 publications

(51 citation statements)

References 42 publications

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“…3B). Next, we investigated the ability of AhR-deficient macrophages to produce NO and ROS since the members of this group of molecules are major cytotoxic mediators involved in clearance of intracellular pathogens by macrophages (33,34,36). We did not observe any differences in the amounts of NO released by T. cruziinfected macrophages from the two groups of mice (data not shown).…”

Section: Deficiency Of Ahr Results In a Reduction Of In Vitro Ros Promentioning

confidence: 93%

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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Section: Deficiency Of Ahr Results In a Reduction Of In Vitro Ros Promentioning

confidence: 93%

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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“…This receptor is required for maximal interleukin-10 (IL-10) production by NK cells (40). Also, by inhibiting NLRP3 expression in macrophages, AhR reduces the inflammatory response and inhibits apoptosis during infection (41, 42) In dendritic cells, AhR activates SFKs, which phosphorylate IDO, leading to increased enzyme activity and production of tolerogenic kynurenines (43). In the gastrointestinal mucosa, AhR induces IL-22 production by innate lymphoid cells, thereby augmenting the antifungal resistance of gastrointestinal epithelial cells (44).…”

Section: Discussionmentioning

confidence: 99%

The Aryl Hydrocarbon Receptor Governs Epithelial Cell Invasion during Oropharyngeal Candidiasis

Solis

Swidergall

Bruno

et al. 2017

mBio

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Oropharyngeal candidiasis (OPC), caused predominantly by Candida albicans, is a prevalent infection in patients with advanced AIDS, defects in Th17 immunity, and head and neck cancer. A characteristic feature of OPC is fungal invasion of the oral epithelial cells. One mechanism by which C. albicans hyphae can invade oral epithelial cells is by expressing the Als3 and Ssa1 invasins that interact with the epidermal growth factor receptor (EGFR) on epithelial cells and stimulate endocytosis of the organism. However, the signaling pathways that function downstream of EGFR and mediate C. albicans endocytosis are poorly defined. Here, we report that C. albicans infection activates the aryl hydrocarbon receptor (AhR), leading to activation of Src family kinases (SFKs), which in turn phosphorylate EGFR and induce endocytosis of the fungus. Furthermore, treatment of oral epithelial cells with interferon gamma inhibits fungal endocytosis by inducing the synthesis of kynurenines, which cause prolonged activation of AhR and SFKs, thereby interfering with C. albicans-induced EGFR signaling. Treatment of both immunosuppressed and immunocompetent mice with an AhR inhibitor decreases phosphorylation of SFKs and EGFR in the oral mucosa, reduces fungal invasion, and lessens the severity of OPC. Thus, our data indicate that AhR plays a central role in governing the pathogenic interactions of C. albicans with oral epithelial cells during OPC and suggest that this receptor is a potential therapeutic target.

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“…It is conceivable that Nos1 expression in murine macrophages infected with this mutant can restrict its growth via production of NO, which has antimicrobial functions and which is known to induce the DosR regulon. The differential expression of Ahr (aryl hydrocarbon receptor) and genes in this network was also of interest because it is required for bacterial clearance by promoting macrophage survival and reactive oxygen species production (46).…”

Section: Discussionmentioning

confidence: 99%

DosS Is Required for the Complete Virulence of Mycobacterium tuberculosis in Mice with Classical Granulomatous Lesions

Gautam¹,

McGillivray²,

Mehra

et al. 2015

Am J Respir Cell Mol Biol

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Mycobacterium tuberculosis (Mtb) must counter hypoxia within granulomas to persist. DosR, in concert with sensor kinases DosS and DosT, regulates the response to hypoxia. Yet Mtb lacking functional DosR colonize the lungs of C57Bl/6 mice, presumably owing to the lack of organized lesions with sufficient hypoxia in that model. We compared the phenotype of the D-dosR, D-dosS, and D-dosT mutants to Mtb using C3HeB/FeJ mice, an alternate mouse model where lesions develop hypoxia. C3HeB/FeJ mice were infected via aerosol. The progression of infection was analyzed by tissue bacterial burden and histopathology. A measure of the comparative global immune responses was also analyzed. Although D-dosR and D-dosT grew comparably to wild-type Mtb, D-dosS exhibited a significant defect in bacterial burden and pathology in vivo, accompanied by ablated proinflammatory response. D-dosS retained the ability to induce DosR. The D-dosS mutant was also attenuated in murine macrophages ex vivo, with evidence of reduced expression of the proinflammatory signature. Our results show that DosS, but not DosR and DosT, is required by Mtb to survive in C3HeB/FeJ mice.The attenuation of D-dosS is not due to its inability to induce the DosR regulon, nor is it a result of the accumulation of hypoxia. That the in vivo growth restriction of D-dosS could be mimicked ex vivo suggested sensitivity to macrophage oxidative burst. Anoxic caseous centers within tuberculosis lesions eventually progress to cavities. Our results provide greater insight into the molecular mechanisms of Mtb persistence within host lungs.Keywords: Mycobacterium tuberculosis; hypoxia; response regulator; sensor kinase; latency Clinical RelevanceOur research indicates that the C3HeB/FeJ mouse model is appropriate for the study of Mycobacterium tuberculosis pathogenesis because it reveals attenuation in the D-dosS mutation. It appears that this attenuation is not the result of hypoxia in lung granulomas.

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Aryl hydrocarbon receptor protects against bacterial infection by promoting macrophage survival and reactive oxygen species production

Cited by 58 publications

References 42 publications

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

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

The Aryl Hydrocarbon Receptor Governs Epithelial Cell Invasion during Oropharyngeal Candidiasis

DosS Is Required for the Complete Virulence of Mycobacterium tuberculosis in Mice with Classical Granulomatous Lesions

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