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

Barroso, Andréia; Gualdrón‐López, Melisa; Esper, Lísia; Brant, Fátima; Araujo, Ronan Ricardo S.; Carneiro, Mariângela; Ávila, Thiago Vinicius; Souza, Danielle G.; Vieira, Leda Quércia; Rachid, Milene Alvarenga; Tanowitz, Herbert B.; Teixeira, Mauro Martins; Machado, Fabiana S.

doi:10.1128/iai.00575-16

Cited by 34 publications

(26 citation statements)

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“…Analogous results were observed in Listeria monocytogenes but not in Trypanosoma cruzi infected AhR −/− mice. Interesting, in T. cruzi infection, an increased NO production by AhR-deficient mice was concomitant with reduced pathogen loads 53 , an observation not reproduced in our study. Despite the increased NO levels detected in AhR −/− mice, an increased fungal burden was observed, suggesting that in pulmonary PCM the Trp depletion mediated by the enzymatic activity of IDO-1 exerts a more efficient fungicidal mechanism than that mediated by NO.…”

Section: Discussioncontrasting

confidence: 67%

Pulmonary paracoccidioidomycosis in AhR deficient hosts is severe and associated with defective Treg and Th22 responses

Araújo

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Veldhoen

et al. 2020

Sci Rep

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AhR is a ligand-activated transcription factor that plays an important role in the innate and adaptive immune responses. In infection models, it has been associated with host responses that promote or inhibit disease progression. In pulmonary paracoccidioidomycosis, a primary fungal infection endemic in Latin America, immune protection is mediated by Th1/Th17 cells and disease severity with predominant Th2/Th9/Treg responses. Because of its important role at epithelial barriers, we evaluate the role of AhR in the outcome of a pulmonary model of paracoccidioidomycosis. AhR −/− mice show increased fungal burdens, enhanced tissue pathology and mortality. During the infection, AhR −/− mice have more pulmonary myeloid cells with activated phenotype and reduced numbers expressing indoleamine 2,3 dioxygenase 1. AhR-deficient lungs have altered production of cytokines and reduced numbers of innate lymphoid cells (NK, ILC3 and NCR IL-22). The lungs of AhR −/− mice showed increased presence Th17 cells concomitant with reduced numbers of Th1, Th22 and Foxp3 + Treg cells. Furthermore, treatment of infected WT mice with an AhR-specific antagonist (CH223191) reproduced the main findings obtained in AhR −/− mice. Collectively our data demonstrate that in pulmonary paracoccidioidomycosis AhR controls fungal burden and excessive tissue inflammation and is a possible target for antifungal therapy. AhR is a ligand-activated cytosolic transcription factor with known involvement in the metabolism of xenobiotic compounds. It mediates the toxic effects of man-made aryl hydrocarbons including 2,3,7,8-tetrachlorodibenzenop-dioxin (also known as TCDD or Dioxin) 1 but can also be activated by a diverse set of endogenous and exogenous ligands 2. In steady state, AhR remains in the cytoplasm as part of an inactive complex composed of several chaperone proteins 3. Upon ligand binding, AhR is released, translocate to the nucleus and heterodimerizes with its partner AhR Nuclear Translocator (ARNT). The heterodimer can bind genomic regions containing its binding motif, thereby inducing the transcription of target genes including detoxifying enzymes of the cytochrome P 450 family 4 and the AhR repressor that disrupts the AhR/ARNT complex and attenuates AhR signaling. In the nucleus, AhR can interact with several transcription factors that regulate its activity 3. The degree of AhR activation may dependent on the structure and receptor affinity of the ligand. Several tryptophan (Trp) degradation products such as Kynurenine (Kyn), produced by the enzymatic action of indoleamine 2,3 dioxygenase (IDO-1) and 6-formylindolo[3,2-b] carbazole (FICZ), a tryptophan condensation product, are well known AhR ligands 5,6. AhR is expressed by cells of the innate and adaptive immune system and participates in the control of cell proliferation, differentiation and cytokine secretion 6-10. In 2008, different laboratories showed that AhR contributes to the differentiation of Th17 and regulatory T cells (Treg) 8-10. Interestingly, two different AhR ligands (TCDD and...

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Section: Discussioncontrasting

confidence: 67%

Pulmonary paracoccidioidomycosis in AhR deficient hosts is severe and associated with defective Treg and Th22 responses

Araújo

Preite

Veldhoen

et al. 2020

Sci Rep

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“…Aryl hydrocarbon receptor ( Ahr ) is a gene known to promote ROS production in response to infections such as listeriosis [ 42 ]; its genetic absence decreases T . cruzi parasite burden as well as ROS production in infected macrophages [ 43 ]. Also, the treatment of infected ES mice with melatonin [ 44 ] or curcumin [ 45 ], both known to activate antioxidant defenses, reduced parasite burden in blood and heart tissue.…”

Section: Evidences In Favor Of Ros As a Promoter Of T mentioning

confidence: 99%

ROS and Trypanosoma cruzi: Fuel to infection, poison to the heart

2018

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The activation of macrophage respiratory burst in response to infection with Trypanosoma cruzi inflicts oxidative damage to the host’s tissues. For decades, the role of reactive oxygen species (ROS) in the elimination of T. cruzi was taken for granted, but recent evidence suggests parasite growth is stimulated in oxidative environments. It is still a matter of debate whether indeed oxidative environments provide ideal conditions (e.g., iron availability in macrophages) for T. cruzi growth and whether indeed ROS signals directly to stimulate growth. Nitric oxide (NO) and ROS combine to form peroxynitrite, participating in the killing of phagocytosed parasites by activated macrophages. In response to infection, mitochondrial ROS are produced by cardiomyocytes. They contribute to oxidative damage that persists at the chronic stage of infection and is involved in functional impairment of the heart. In this review, we discuss how oxidative stress helps parasite growth during the acute stage and how it participates in the development of cardiomyopathy at the chronic stage.

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“…both up- and down-regulation of ROS formation. This delicate balance occurs in such seemingly unrelated signaling pathways as: circadian rhythmicity (Patel et al , 2014); enhanced immune response exhibiting increased levels of inflammatory cytokines and decreased Socs2 (suppression of cytokine signaling-2) expression — that had been observed in zymosan-caused peritonitis in liver of Cyp1a1 / 1a2 / 1b1(−/−) triple-knockout mice (Nebert and Karp, 2008) — and infectious myocarditis (Barroso et al , 2016); inflammatory plaque formation during atherosclerosis (Marinkovic et al , 2013; Uno et al , 2014; Pernomian and da Silva, 2015); hepatic steatosis (Gooley, 2016; Mellor et al , 2016; Nault et al , 2017); atopic dermatitis associated with a dysfunctional skin barrier (Nomura and Kabashima, 2016); and aging and age-associated diseases (Gasiewicz et al , 2014; Patel et al , 2014). …”

Section: Ahr and Cell-signaling Pathwaysmentioning

confidence: 99%

Aryl hydrocarbon receptor (AHR): “pioneer member” of the basic-helix/loop/helix per - Arnt - sim (bHLH/PAS) family of “sensors” of foreign and endogenous signals

Nebert

2017

Progress in Lipid Research

216

191

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The basic-helix-loop-helix Per-Arnt-Sim (bHLH/PAS) family comprises many transcription factors, found throughout all three kingdoms of life; bHLH/PAS members “sense” innumerable intracellular and extracellular “signals” — including endogenous compounds, foreign chemicals, gas molecules, redox potential, photons (light), gravity, heat, and osmotic pressure. These signals then initiate downstream signaling pathways involved in responding to that signal. The term “PAS”, abbreviation for “Per-Arnt-Sim” was first coined in 1991. Although the mouse Arnt gene was not identified until 1991, evidence of its co-transcriptional binding partner, aryl hydrocarbon receptor (AHR), was first reported in 1974 as a “sensor” of foreign chemicals, up-regulating cytochrome P450 family 1 (CYP1) and other enzyme activities that usually metabolize the signaling chemical. Within a few years, AHR was proposed also to participate in inflammation. The mouse [Ah] locus was shown (1973–1989) to be relevant to chemical carcinogenesis, mutagenesis, toxicity and teratogenesis, the mouse Ahr gene was cloned in 1992, and the first Ahr(−/−) knockout mouse line was reported in 1995. After thousands of studies from the early 1970s to present day, we now realize that AHR participates in dozens of signaling pathways involved in critical-life processes, affecting virtually every organ and cell-type in the animal, including many invertebrates.

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

Cited by 34 publications

References 49 publications

Pulmonary paracoccidioidomycosis in AhR deficient hosts is severe and associated with defective Treg and Th22 responses

Pulmonary paracoccidioidomycosis in AhR deficient hosts is severe and associated with defective Treg and Th22 responses

ROS and Trypanosoma cruzi: Fuel to infection, poison to the heart

Aryl hydrocarbon receptor (AHR): “pioneer member” of the basic-helix/loop/helix per - Arnt - sim (bHLH/PAS) family of “sensors” of foreign and endogenous signals

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