Oxidative stress fuels Trypanosoma cruzi infection in mice

Paiva, Cláudia N.; Feijó, Daniel F.; Dutra, Fabianno F.; Carneiro, Vitor Coutinho; Freitas, Guilherme B. de; Alves, Letícia S.; Mesquita, Jacilene; Fortes, Guilherme B.; Figueiredo, Rodrigo T.; Souza, Heitor; Fantappíé, Marcelo Rosado; Lannes‐Vieira, Joseli; Bozza, Marcelo T.

doi:10.1172/jci58525

Cited by 147 publications

(203 citation statements)

References 69 publications

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“…We consistently found decreased ROS production by AhR KO macrophages in the presence of zymosan, a stimulus that typically induces ROS in the setting of phagocytosis (44). Previously, it was reported that AhR contributes substantially to ROS production when cells are persistently activated by TCDD and that this is mediated by persistent CYP1 expression (19,45,46). The contradiction between ROS production by spleen cells from infected mice ex vivo and by macrophages stimulated in vitro could be explained by the wide range of ligands that can differentially activate AhR and the vast quantity of genes that are under AhR control (6).…”

Section: Discussionsupporting

confidence: 65%

“…Similarly, macrophages from AhR KO mice controlled parasite replication more effectively than WT cells. Parasitemia control is achieved via several immune mechanisms (18)(19)(20)(21). However, our results strongly suggest that the resistant phenotype observed in AhR KO mice could be explained by factors such as production of larger amounts of systemic NO, an important molecule involved in parasite clearance (42).…”

Section: Discussionmentioning

confidence: 94%

“…Although important in the inhibition of parasite replication, ROS may result in host cell damage. Interestingly, some reports suggest that ROS-derived metabolites may promote pathogen replication (19). Importantly, both NO and ROS are capable of promoting peroxynitrite-mediated T. cruzi clearance in macrophages (20,21).…”

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confidence: 99%

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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: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 94%

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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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“…When released from hemeproteins, however, free heme becomes highly cytotoxic, owing mainly to its pro-oxidant properties, and participates in the pathogenesis of inflammatory/ hemolytic diseases such as malaria and sepsis (1,2). This in turn induces an equally potent cellular response to cope with the stress, minimize redox imbalance, and maintain homeostasis (33). We show here that the stress response triggered by heme includes the transient assembly of p62 + /Ub + protein aggregates known as ALIS.…”

Section: Discussionmentioning

confidence: 80%

Protein aggregation as a cellular response to oxidative stress induced by heme and iron

Vasconcellos

Dutra

Siqueira

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Hemolytic diseases include a variety of conditions with diverse etiologies in which red blood cells are destroyed and large amounts of hemeproteins are released. Heme has been described as a potent proinflammatory molecule that is able to induce multiple innate immune responses, such as those triggered by TLR4 and the NLRP3 inflammasome, as well as necroptosis in macrophages. The mechanisms by which eukaryotic cells respond to the toxic effects induced by heme to maintain homeostasis are not fully understood, however. Here we describe a previously uncharacterized cellular response induced by heme: the formation of p62/SQTM1 aggregates containing ubiquitinated proteins in structures known as aggresome-like induced structures (ALIS). This action is part of a response driven by the transcription factor NRF2 to the excessive generation of reactive oxygen species induced by heme that results in the expression of genes involved in antioxidant responses, including p62/SQTM1. Furthermore, we show that heme degradation by HO-1 is required for ALIS formation, and that the free iron released on heme degradation is necessary and sufficient to induce ALIS. Moreover, ferritin, a key protein in iron metabolism, prevents excessive ALIS formation. Finally, in vivo, hemolysis promotes an increase in ALIS formation in target tissues. Our data unravel a poorly understood aspect of the cellular responses induced by heme that can be explored to better understand the effects of free heme and free iron during hemolytic diseases such as sickle cell disease, dengue fever, malaria, and sepsis.autophagy | p62/SQSTM1 | ALIS | heme | iron

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“…However, this is clearly not the whole story. In this issue of the JCI, Paiva et al (1) demonstrate that antioxidant responses actually suppress infections with Trypanosoma cruzi, a protozoan parasite that seems to thrive in an oxidative environment. Earlier studies with viruses and bacterial pathogens suggested a similar scenario, but those observations were mostly attributed to a role of antioxidant pathways in innate immunity.…”

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confidence: 99%

Oxidative stress and intracellular infections: more iron to the fire

Andrews¹

2012

J. Clin. Invest.

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Oxidative stress fuels Trypanosoma cruzi infection in mice

Cited by 147 publications

References 69 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

Protein aggregation as a cellular response to oxidative stress induced by heme and iron

Oxidative stress and intracellular infections: more iron to the fire

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