Treatment of chronically Trypanosoma cruzi-infected mice with a CCR1/CCR5 antagonist (Met-RANTES) results in amelioration of cardiac tissue damage.
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.
Medeiros
Gabriela A
GA
Laboratório de Biologia das Interações, Instituto Oswaldo Cruz -Fiocruz, Av. Brasil 4365, Rio de Janeiro 21045-900, Brazil.
Silvério
Jaline C
JC
Marino
Ana Paula M P
AP
Roffê
Ester
E
Vieira
Valeska
V
Kroll-Palhares
Karina
K
Carvalho
Cristiano E
CE
Silva
Andréa Alice
AA
Teixeira
Mauro M
MM
Lannes-Vieira
Joseli
J
D000818:Animals; D065100:CCR5 Receptor Antagonists; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002598:Chagas Cardiomyopathy / Q000188:drug therapy / Q000473:pathology; D014355:Chagas Disease / Q000188:drug therapy* / Q000473:pathology*; D018946:Chemokine CCL5 / Q000494:pharmacology / Q000627:therapeutic use*; D018031:Connexin 43 / Q000032:analysis; D005260:Female; D006321:Heart / Q000469:parasitology; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000096:biosynthesis; D018793:Interleukin-13 / Q000096:biosynthesis; D051379:Mice; D008809:Mice, Inbred C3H; D009206:Myocardium / Q000737:chemistry / Q000473:pathology*; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors*; D014349:Trypanosoma cruzi / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D065100:CCR5 Receptor Antagonists; C515301:Ccr1 protein, mouse; D018946:Chemokine CCL5; D018031:Connexin 43; D007155:Immunologic Factors; D018793:Interleukin-13; C108335:RANTES, Met-; D054389:Receptors, CCR1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10