Toll-like receptor-2 and interleukin-6 mediate cardiomyocyte protection from apoptosis during Trypanosoma cruzi murine infection

Ponce, Nicolás; Cano, Roxana Carolina; Silva, Eugenio Antonio Carrera; Lima, Ana Paula; Gea, Susana; Aoki, María Pilar

doi:10.1007/s00430-011-0216-z

Cited by 29 publications

(30 citation statements)

References 37 publications

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“…Moreover, IL-6 diminished the nitration rate and improved the survival of CD8+ T cells. In agreement with this result, we have previously shown that IL-6 acts as a survival factor for infected target cells (28, 29). We have observed that IL-6 regulates IL-1β-induced NO production, and that excessive oxidative stress accounts for the increased mortality of T. cruzi -infected IL6KO mice (unpublished results).…”

Section: Discussionsupporting

confidence: 87%

IL-6 Improves the Nitric Oxide-Induced Cytotoxic CD8+ T Cell Dysfunction in Human Chagas Disease

Sanmarco

Visconti²,

Eberhardt

et al. 2016

Front. Immunol.

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Reactive oxygen and nitrogen species are important microbicidal agents and are also involved in lymphocyte unresponsiveness during experimental infections. Many of the biological effects attributed to nitric oxide are mediated by peroxynitrites, which induce the nitration of immune cells, among others. Our group has demonstrated that nitric oxide is involved in the suppressive activity of myeloid-derived suppressor cells in Trypanosoma cruzi-infected mice, with a higher number of CD8+ T cells suffering surface-nitration compared to uninfected controls. Studying the functional and phenotypic features of peripheral CD8+ T cells from chagasic patients and human cells experimentally infected with T. cruzi, we found that different regulatory mechanisms impaired the effector functions of T cytotoxic population from seropositive patients. Peripheral leukocytes from chagasic patients showed increased nitric oxide production concomitant with increased tyrosine nitration of CD8+ T cells. Additionally, this cytotoxic population exhibited increased apoptotic rate, loss of the TCRζ-chain, and lower levels of CD107a, a marker of degranulation. Strikingly, IL-6 stimulation of in vitro-infected peripheral blood mononuclear cells obtained from healthy donors, blunted T. cruzi-induced nitration of CD3+CD8+ cells, and increased their survival. Furthermore, the treatment of these cultures with an IL-6 neutralizing antibody increased the percentage of T. cruzi-induced CD8+ T cell nitration and raised the release of nitric oxide. The results suggest that the under-responsiveness of cytotoxic T cell population observed in the setting of long-term constant activation of the immune system could be reverted by the pleiotropic actions of IL-6, since this cytokine improves its survival and effector functions.

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Section: Discussionsupporting

confidence: 87%

IL-6 Improves the Nitric Oxide-Induced Cytotoxic CD8+ T Cell Dysfunction in Human Chagas Disease

Sanmarco

Visconti²,

Eberhardt

et al. 2016

Front. Immunol.

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“…Regarding the increased levels of IL-6 detected in APCP-treated hearts, it is important to stress that this pleiotropic cytokine is a cardioprotective factor. In this sense, we have reported that IL-6 is secreted by cardiomyocytes after T. cruzi recognition, and it acts as a key survival factor for these target cells during the infection (43)(44)(45).…”

Section: Discussionmentioning

confidence: 98%

CD73 Inhibition Shifts Cardiac Macrophage Polarization toward a Microbicidal Phenotype and Ameliorates the Outcome of Experimental Chagas Cardiomyopathy

Ponce

Sanmarco

Eberhardt

et al. 2016

The Journal of Immunology

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Increasing evidence demonstrates that generation of extracellular adenosine from ATP, which is hydrolyzed by the CD39/CD73 enzyme pair, attenuates the inflammatory response and deactivates macrophage antimicrobial mechanisms. Although CD73 is emerging as a critical pathway and therapeutic target in cardiovascular disorders, the involvement of this ectonucleotidase during myocardial infection has not been explored. Using a murine model of infection with Trypanosoma cruzi, the causal agent of Chagas cardiomyopathy, we observed a sudden switch from the classical M1 macrophage (microbicidal) phenotype toward an alternative M2 (repairing/anti-inflammatory) phenotype that occurred within the myocardium very shortly after BALB/c mice infection. The observed shift in M1/M2 rate correlated with the cardiac cytokine milieu. Considering that parasite persistence within myocardium is a necessary and sufficient condition for the development of the chronic myocarditis, we hypothesized that CD73 activity may counteract cardiac macrophage microbicidal polarization, rendering the local immune response less effective. In fact, a transient treatment with a specific CD73 inhibitor (adenosine 5′-α,β-methylene-diphosphate) enhanced the microbicidal M1 subset predominance, diminished IL-4– and IL-10–producing CD4+ T cells, promoted a proinflammatory cytokine milieu, and reduced parasite load within the myocardium during the acute phase. As a direct consequence of these events, there was a reduction in serum levels of creatine kinase muscle–brain isoenzyme, a myocardial-specific injury marker, and an improvement in the electrocardiographic characteristics during the chronic phase. Our results demonstrate that this purinergic system drives the myocardial immune response postinfection and harbors a promising potential as a therapeutic target.

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“…Deletion of IL‐6 was consistently shown to be beneficial against fibrotic heart disease 29. However, IL‐6 seems to exert pleiotropic effects and control the balance between anti‐ and proapoptotic pathways 30, 31. The exact role of IL‐6 signaling in atrial cardiomyocyte apoptosis induced by RA needs to be further investigated in future studies.…”

Section: Discussionmentioning

confidence: 99%

Atrial Fibrillation Promotion in a Rat Model of Rheumatoid Arthritis

Dai

Wang

Yin

et al. 2017

JAHA

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BackgroundThe prevalence of atrial fibrillation (AF) is significantly higher in rheumatoid arthritis (RA) patients, but the underlying mechanisms remain poorly understood. The goal of this study was to assess the effects of RA on AF susceptibility and atrial arrhythmogenic remodeling in a rat model of RA.Methods and ResultsCollagen‐induced arthritis was induced in rats by immunization with type II collagen in Freund's incomplete adjuvant. Among the rats that developed arthritis, AF susceptibility and atrial remodeling were examined 8 weeks after the primary immunization. AF inducibility and duration were substantially increased in collagen‐induced arthritis rats, and AF duration was significantly and positively correlated with the serum IL‐6 and TNF‐α levels. Rats with collagen‐induced arthritis showed prolonged atrial conduction time with no changes in the atrial effective refractory period. Atrial conduction delay was accompanied by significantly increased atrial fibrosis. In addition, atrial structural and autonomic remodeling, including left atrial dilation, apoptosis and autophagy of atrial myocytes, and atrial heterogeneous sympathetic hyperinnervation, was observed. Interestingly, we found that collagen‐induced arthritis had no significant effects on connexins, Nav1.5, and the main ion channels' protein expressions in atria.ConclusionsWe demonstrated that RA increased AF susceptibility by inducing AF‐promoting atrial remodeling. This study may provide insights into mechanisms underlying RA‐induced AF and validate a model that is suitable for further mechanistic and therapeutic exploration.

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Toll-like receptor-2 and interleukin-6 mediate cardiomyocyte protection from apoptosis during Trypanosoma cruzi murine infection

Cited by 29 publications

References 37 publications

IL-6 Improves the Nitric Oxide-Induced Cytotoxic CD8+ T Cell Dysfunction in Human Chagas Disease

IL-6 Improves the Nitric Oxide-Induced Cytotoxic CD8+ T Cell Dysfunction in Human Chagas Disease

CD73 Inhibition Shifts Cardiac Macrophage Polarization toward a Microbicidal Phenotype and Ameliorates the Outcome of Experimental Chagas Cardiomyopathy

Atrial Fibrillation Promotion in a Rat Model of Rheumatoid Arthritis

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