Regulatory role of Toll-like receptor 2 during infection with Trypanosoma cruzi.
Previous studies have emphasized the role of Toll-like receptors (TLRs) and myeloid differentiation factor 88 (MyD88) during infection with protozoan parasites. TLR2 was shown to be important for induction of cytokine synthesis by macrophages exposed to the purified glycosylphosphatidylinositol (GPI)-anchored mucin-like glycoproteins of Trypanosoma cruzi trypomastigotes (tGPIm). On the other hand, MyD88(-/-) mice, but not TLR2(-/-) mice, showed impaired cytokine production and resistance to infection with T. cruzi parasites. Here we evaluate the importance of MyD88 and TLR2 in MAPK activation and cytokine synthesis by macrophages exposed to live T. cruzi parasites and compared to tGPIm. The absence of MAPK phosphorylation in TLR2- and MyD88-deficient macrophages exposed to tGPIm correlated with the incapacity to induce cytokine release in these cells. In contrast, activation of MAPK and synthesis of pro-inflammatory cytokines were not abrogated in TLR2-deficient macrophages exposed to live T. cruzi parasites. We also showed that pretreatment with tGPIm significantly reduces cytokine release by macrophages in response to T. cruzi in a TLR2-dependent manner. Consistently, TLR2(-/-) mice were shown to produce enhanced levels of cytokines upon in vivo challenge with T. cruzi parasites. Together, these results suggest the involvement of additional TLR(s) in the pro-inflammatory response of macrophages to whole parasites, and that, in vivo, TLR2 may have a predominant immunoregulatory role during acute infection with T. cruzi parasites.
Ropert
Catherine
C
Laboratory of Immunopathology, Centro de Pesquisas René Rachou, FIOCRUZ, Av. Augusto de Lima 1715, Barro Preto, 30190-002 Belo Horizonte, MG, Brazil. cropert@hotmail.com
Gazzinelli
Ricardo Tostes
RT
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology; D014355:Chagas Disease / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D006790:Host-Parasite Interactions / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048290:Mitogen-Activated Protein Kinase 11 / Q000096:biosynthesis; D009077:Mucins / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88; D010273:Parasitic Diseases, Animal / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D015800:Protozoan Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology; D051195:Toll-Like Receptor 2; D014349:Trypanosoma cruzi / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D016207:Cytokines; D008070:Lipopolysaccharides; D009077:Mucins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D048290:Mitogen-Activated Protein Kinase 11; D048051:p38 Mitogen-Activated Protein Kinases