ABSTRACT
The inflammatory response in the myocardium is an important aspect of the pathogenesis of Chagas' heart disease raised by Trypanosoma cruzi. CD40, a transmembrane type I receptor belonging to the tumor necrosis factor receptor (TNFR) family, is expressed in a broad spectrum of cell types and is crucial in several inflammatory and autoimmune diseases. Activation of CD40 through ligation to CD40L (CD154) induces multiple effects, including the secretion of proinflammatory molecules. In the present study, we examined the ability of T. cruzi to trigger the expression of CD40 in cardiac myocytes in vitro and in a murine model of chagasic cardiomyopathy. Our results indicate, for the first time, that T. cruzi is able to induce the expression of CD40 in HL-1 murine cardiomyocytes. Moreover, ligation of CD40 receptor upregulated interleukin-6 (IL-6), associated with inflammation. Furthermore, the induction of this costimulatory molecule was demonstrated in vivo in myocardium of mice infected with T. cruzi. This suggests that CD40-bearing cardiac muscle cells could interact with CD40L-expressing lymphocytes infiltrating the heart, thus contributing to inflammatory injury in chagasic cardiomyopathy.
Subject(s)
CD40 Antigens/metabolism , Chagas Cardiomyopathy/parasitology , Interleukin-6/metabolism , Myocytes, Cardiac/immunology , Trypanosoma cruzi/physiology , Animals , CD40 Antigens/genetics , Cells, Cultured , Chagas Cardiomyopathy/pathology , Disease Models, Animal , Female , Gene Expression Regulation , Interferon-gamma/pharmacology , Mice , Mice, Inbred C3H , Myocardium/pathology , Myocytes, Cardiac/parasitology , RNA, Messenger/metabolism , Real-Time Polymerase Chain Reaction , Trypanosoma cruzi/immunologyABSTRACT
Heart failure and sudden death are the most common causes of death in patients with Chagas' disease. The main drug available for Chagas treatment is benznidazole, which eradicates Trypanosoma cruzi parasites during the acute stage of infection. However, its effectiveness during the chronic phase remains unclear. Ganglioside GM1 administration in chronically infected patients resulted to be an effective treatment for the cardiac manifestations of Chagas' disease. However, the precise mechanisms of GM1-induced improvement during chronic T. cruzi infection still remain unknown. The aim of the present study was to evaluate the potential benefits of ganglioside GM1 treatment during the chronic stage of murine chagasic infection, analyzing its influence on myocardial pathology as well as its immunomodulatory effects. The results obtained showed that GM1 therapy diminished the extent of myocardial fibrosis induced by T. cruzi in chronically infected mice. In addition, GM1 treatment resulted in a significant reduction in the myocardial expression of the fibrogenic cytokine TGF-ß as well as the proinflammatory cytokines and chemokines IFN-γ, TNF-α and CCL5/RANTES. Our experimental data indicate that GM1 could be a promising immunomodulatory agent with capacity to limit the inflammatory process leading to myocardial tissue damage in chronic chagasic patients.
Subject(s)
Chagas Cardiomyopathy/drug therapy , G(M1) Ganglioside/pharmacology , Immunologic Factors/pharmacology , Trypanosoma cruzi/drug effects , Animals , Chagas Cardiomyopathy/genetics , Chagas Cardiomyopathy/immunology , Chagas Cardiomyopathy/pathology , Chemokine CCL5/antagonists & inhibitors , Chemokine CCL5/genetics , Female , Fibrosis/drug therapy , Fibrosis/genetics , Fibrosis/pathology , Interferon-gamma/antagonists & inhibitors , Interferon-gamma/genetics , Mice , Mice, Inbred BALB C , Myocardium/metabolism , Myocardium/pathology , Transforming Growth Factor beta/antagonists & inhibitors , Transforming Growth Factor beta/genetics , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/geneticsABSTRACT
OBJECTIVE: Chagas' disease is caused by persistent Trypanosoma cruzi infection in muscle cells that ultimately results in chronic inflammation and tissue destruction. The goal of this study was to determine the expression of different chemokines and their receptors, as well as proinflammatory cytokines and inducible nitric oxide synthase, in muscles from mice acutely infected with T. cruzi. METHODS: Histological, semiquantitative reverse transcriptase polymerase chain reaction and immunohistochemical studies were performed on skeletal muscle and myocardium of BALB/c mice infected with T. cruzi, RA strain. RESULTS: Early induction of muscular mRNA expression for CCL5/CCR5 and CXCL9/CXCR3, as well as for iNOS, IFN-gamma, TNF-alpha and MIF, was demonstrated accompanied by progressive increases in parasitism and leukocyte recruitment. Protein overexpression for MIF and CCL5/CCR5 was also verified in the infected muscles. CONCLUSIONS: In muscles from acutely T. cruzi RA-infected mice, upregulated gene expression of proinflammatory chemokines, chemokine receptors, cytokines and iNOS is associated with the severity of parasite burden and myopathic alterations. Compared to the heart, striated muscles displayed differential timing of expression of several inflammatory mediators throughout acute infection. Our findings suggest that enhanced early production of these factors could contribute to T. cruzi-dependent inflammatory damage to skeletal muscles.