RESUMEN
The comprehension of the molecular mechanisms leading to Trypanosoma cruzi-elicited heart dysfunction might contribute to design novel therapeutic strategies aiming to ameliorate chronic Chagas disease cardiomyopathy. In C3H/He mice infected with the low virulence T. cruzi Colombian strain, the persistent cardiac inflammation composed mainly of CCR5(+) T lymphocytes parallels the expression of CC-chemokines in a pro-inflammatory IFN-gamma and TNF-alpha milieu. The chronic myocarditis is accompanied by increased frequency of peripheral CCR5(+)LFA-1(+) T lymphocytes. The treatment of chronically T. cruzi-infected mice with Met-RANTES, a selective CCR1/CCR5 antagonist, led to a 20-30% decrease in CD4(+) cell numbers as well as IL-10, IL-13 and TNF-alpha expression. Further, Met-RANTES administration impaired the re-compartmentalization of the activated CD4(+)CCR5(+) lymphocytes. Importantly, Met-RANTES treatment resulted in significant reduction in parasite load and fibronectin deposition in the heart tissue. Moreover, Met-RANTES treatment significantly protected T. cruzi-infected mice against connexin 43 loss in heart tissue and CK-MB level enhancement, markers of heart dysfunction. Thus, our results corroborate that therapeutic strategies based on the modulation of CCR1/CCR5-mediated cell migration and/or effector function may contribute to cardiac tissue damage limitation during chronic Chagas disease.
Asunto(s)
Antagonistas de los Receptores CCR5 , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/patología , Quimiocina CCL5/uso terapéutico , Factores Inmunológicos/uso terapéutico , Miocardio/patología , Receptores CCR1/antagonistas & inhibidores , Trypanosoma cruzi/fisiología , Animales , Linfocitos T CD4-Positivos/inmunología , Cardiomiopatía Chagásica/tratamiento farmacológico , Cardiomiopatía Chagásica/patología , Quimiocina CCL5/farmacología , Conexina 43/análisis , Femenino , Corazón/parasitología , Factores Inmunológicos/farmacología , Interleucina-10/biosíntesis , Interleucina-13/biosíntesis , Ratones , Ratones Endogámicos C3H , Miocardio/química , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
BACKGROUND: Comprehension of the pathogenesis of Trypanosoma cruzi-elicited myocarditis is crucial to delineate strategies aimed at ameliorating the inflammation associated with heart dysfunction. The augmented expression of CC chemokines, especially CCL5/RANTES and CCL3/MIP-1alpha, in the hearts of infected mice suggests a role for CC chemokines and their receptors in the pathogenesis of T cruzi-elicited myocarditis. METHODS AND RESULTS: We report that during the early phase of infection in C3H/HeJ mice infected with 100 blood trypomastigotes of T cruzi, most of the inflammatory cells invading the heart tissue were CD8+ cells and expressed CCR5, a CCL5/RANTES, and CCL3/MIP1-alpha receptor. Furthermore, peripheral blood CD8+ T lymphocytes displayed increased expression of CCR5. These findings led us to use Met-RANTES, a selective CCR1 and CCR5 antagonist, to modulate the acute T cruzi-elicited myocarditis. Met-RANTES treatment did not interfere with parasitism but significantly decreased the numbers of CD4+ and CD8+ T cells, CCR5+, and interleukin-4+ cells invading the heart, paralleling the diminished deposition of fibronectin. Moreover, Met-RANTES treatment resulted in increased survival of infected animals, compared with saline treatment. CONCLUSIONS: These results indicate that the massive influx of CCR5+ cells into cardiac tissue is not crucial for cell-mediated anti-T cruzi immunity but appears to be critical for pathogenesis of T cruzi-elicited myocarditis. Thus, CC chemokine receptors might become an attractive therapeutic target for further evaluation during T cruzi infection.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Cardiomiopatía Chagásica/tratamiento farmacológico , Quimiocina CCL5/análogos & derivados , Quimiocina CCL5/metabolismo , Quimiocina CCL5/uso terapéutico , Activación de Linfocitos , Proteínas Inflamatorias de Macrófagos/metabolismo , Miocarditis/tratamiento farmacológico , Animales , Antagonistas de los Receptores CCR5 , Linfocitos T CD4-Positivos/inmunología , Cardiomiopatía Chagásica/sangre , Cardiomiopatía Chagásica/fisiopatología , Quimiocina CCL2/biosíntesis , Quimiocina CCL2/genética , Quimiocina CCL3 , Quimiocina CCL4 , Quimiocina CCL5/antagonistas & inhibidores , Quimiocinas CC/biosíntesis , Quimiocinas CC/genética , Quimiotaxis de Leucocito , Femenino , Fibronectinas/análisis , Interleucina-4/análisis , Proteínas Inflamatorias de Macrófagos/biosíntesis , Proteínas Inflamatorias de Macrófagos/genética , Ratones , Ratones Endogámicos C3H , Miocarditis/sangre , Miocarditis/parasitología , Miocarditis/fisiopatología , ARN Mensajero/biosíntesis , Receptores CCR1 , Receptores CCR5/biosíntesis , Receptores CCR5/genética , Receptores CCR5/fisiología , Receptores de Quimiocina/antagonistas & inhibidores , Receptores de Quimiocina/fisiologíaRESUMEN
Central nervous system (CNS) damage can occur during Trypanosoma cruzi infection, especially in immunosuppressed patients. The enhanced susceptibility of C3H/He mice to CD8-mediated acute meningoencephalitis is associated with higher up-regulation of vascular cell adhesion molecule-1 (VCAM-1) on CNS vascular endothelia than in the less susceptible C57BL/6. Further, in vitro adhesion of activated peripheral blood cells to CNS blood vessels was abrogated by anti-VLA-4 antibodies that also inhibited cell migration into the CNS of T. cruzi-infected mice. Lastly, the reactivation of meningoencephalitis in immunosuppressed chronically infected mice was associated with VCAM-1 up-regulation. Therefore, we hypothesize that VLA-4/VCAM-1 pathway plays a pivotal role in the establishment of T. cruzi-elicited encephalitis.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Infecciones Protozoarias del Sistema Nervioso Central/inmunología , Enfermedad de Chagas/inmunología , Integrina alfa4beta1/fisiología , Meningoencefalitis/inmunología , Transducción de Señal/inmunología , Trypanosoma cruzi/inmunología , Molécula 1 de Adhesión Celular Vascular/fisiología , Animales , Antígenos de Protozoos/análisis , Linfocitos T CD8-positivos/parasitología , Adhesión Celular/inmunología , Movimiento Celular/inmunología , Infecciones Protozoarias del Sistema Nervioso Central/metabolismo , Infecciones Protozoarias del Sistema Nervioso Central/parasitología , Infecciones Protozoarias del Sistema Nervioso Central/patología , Enfermedad de Chagas/metabolismo , Enfermedad de Chagas/parasitología , Enfermedad de Chagas/patología , Enfermedad Crónica , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/inmunología , Endotelio Vascular/parasitología , Endotelio Vascular/patología , Femenino , Predisposición Genética a la Enfermedad , Inmunofenotipificación , Inmunosupresores/administración & dosificación , Integrina alfa4beta1/biosíntesis , Molécula 1 de Adhesión Intercelular/biosíntesis , Leucocitos Mononucleares/química , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/parasitología , Meningoencefalitis/metabolismo , Meningoencefalitis/parasitología , Meningoencefalitis/patología , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Recurrencia , Molécula 1 de Adhesión Celular Vascular/biosíntesisRESUMEN
The participation of cell adhesion molecules (CAMs) in the establishment of autoimmune and infectious myocarditis is an important matter of investigation and may have therapeutic implication. Trypanosoma cruzi infection induces a CD8-mediated myocarditis in patients with severe cardiomyopathy and experimental animals. Previously, we have proposed that this predominance of CD8+ T-cells is, at least in part, consequence of the differential expression of CAMs on circulating CD8+ lymphocytes. In the present study we investigated the participation of CAMs in shaping the phenotypic nature of the autoimmune CD4-mediated myosin-induced and the CD8-mediated T. cruzi-elicited myocarditis. We provide evidence that the prevalence of a certain T-cell subset inside the inflamed heart reflects the differential profile of the adhesion molecules VLA-4, LFA-1, and ICAM-1 displayed on a large proportion of this particular T-cell population in peripheral blood during the early phase of inflammation. Further, the expression of VCAM-1, ligand for VLA-4, and ICAM-1, counter-receptor for LFA-1, was up-regulated on vascular endothelium and paralleled the entrance of inflammatory cells into the cardiac tissue. Thus, this up-regulated expression of receptors-counter-receptors that regulate T-cell transmigration through the vascular endothelium may have an important role in the pathogenesis of the early phase of both autoimmune and infectious myocarditis.