Cooperative activation of TLR2 and bradykinin B-2 receptor is required for induction of type 1 immunity in a mouse model of subcutaneous infection by Trypanosoma cruzi

dc.contributor.authorMonteiro, Ana Carolina
dc.contributor.authorSchmitz, Veronica
dc.contributor.authorSvensjo, Erik
dc.contributor.authorGazzinelli, Ricardo T.
dc.contributor.authorAlmeida, Igor C.
dc.contributor.authorTodorov, Alex
dc.contributor.authorArruda, Luciana B. de
dc.contributor.authorTorrecilhas, Ana Claudia T.
dc.contributor.authorPesquero, Joao B. [UNIFESP]
dc.contributor.authorMorrot, Alexandre
dc.contributor.authorBouskela, Eliete
dc.contributor.authorBonomo, Adriana
dc.contributor.authorLima, Ana Paula C. A.
dc.contributor.authorMueller-Esterl, Werner
dc.contributor.authorScharfstein, Julio
dc.contributor.institutionUniversidade Federal do Rio de Janeiro (UFRJ)
dc.contributor.institutionCtr Pesquisas Rene Rachou Fiocruz
dc.contributor.institutionUniversidade Federal de Minas Gerais (UFMG)
dc.contributor.institutionUniv Texas
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionJohns Hopkins Univ
dc.contributor.institutionUniversidade do Estado do Rio de Janeiro (UERJ)
dc.contributor.institutionUniv Frankfurt
dc.description.abstractWe have previously reported that exogenous bradykinin activates immature dendritic cells (DCs) via the bradykinin B-2 receptor (B2R), thereby stimulating adaptive immunity. In this study, we show that these premises are met in a model of s.c. infection by Trypanosoma cruzi, a protozoan that liberates kinins from kininogens through its major protease, cruzipain. Intensity of B2R-dependent paw edema evoked by trypomastigotes correlated with levels of IL-12 produced by CD11c(+) dendritic cells isolated from draining lymph nodes. The IL-12 response induced by endogenously released kinins was vigorously increased in infected mice pretreated with inhibitors of angiotensin converting enzyme (ACE), a kinin-degrading metallopeptidase. Furthermore, these innate stimulatory effects were linked to B2R-dependent up-regulation of IFN-gamma production by Ag-specific T cells. Strikingly, the trypomastigotes failed to up-regulate type 1 immunity in TLR2(-/-) mice, irrespective of ACE inhibitor treatment. Analysis of the dynamics of inflammation revealed that TLR2 triggering by glycosylphosphatidylinositol-anchored mucins induces plasma extravasaiion, thereby favoring peripheral accumulation of kininogens in sites of infection. Further downstream, the parasites generate high levels of innate kinin signals in peripheral tissues through the activity of cruzipain. The demonstration that the deficient type I immune responses of TLR2(-/-) mice are rescued upon s.c. injection of exogenous kininogens, along with trypomastigotes, supports the notion that generation of kinin danger signals is intensified through cooperative activation of TLR2 and B2R. In summary, we have described a s.c. infection model where type I immunity is vigorously up-regulated by bradykinin, an innate signal whose levels in peripheral tissues are controlled by an intricate interplay of TLR2, B2R, and ACE.en
dc.description.affiliationUniv Fed Rio de Janeiro, Ctr Ciencias Saude, Inst Biofis Carlos Chagas Filho, Lab Imunol Mol, Rio De Janeiro, Brazil
dc.description.affiliationCtr Pesquisas Rene Rachou Fiocruz, Lab Imunopatol, Belo Horizonte, MG, Brazil
dc.description.affiliationUniv Fed Minas Gerais, Inst Ciencias Biol, Dept Bioquim & Imunol, Belo Horizonte, MG, Brazil
dc.description.affiliationUniv Texas, Dept Biol Sci, El Paso, TX 79968 USA
dc.description.affiliationUFRJ, Inst Microbiol, Rio De Janeiro, Brazil
dc.description.affiliationUniv Sao Paulo, Dept Bioquim, Sao Paulo, Brazil
dc.description.affiliationUniv Fed Sao Paulo, Dept Biofis, Sao Paulo, Brazil
dc.description.affiliationJohns Hopkins Univ, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA
dc.description.affiliationUniv Estado Rio de Janeiro, Lab Microcirculacao, Rio De Janeiro, Brazil
dc.description.affiliationUniv Frankfurt, Inst Biochem 2, Sch Med, D-6000 Frankfurt, Germany
dc.description.affiliationUnifespUniv Fed Sao Paulo, Dept Biofis, Sao Paulo, Brazil
dc.description.sourceWeb of Science
dc.identifier.citationJournal Of Immunology. Bethesda: Amer Assoc Immunologists, v. 177, n. 9, p. 6325-6335, 2006.
dc.publisherAmer Assoc Immunologists
dc.relation.ispartofJournal Of Immunology
dc.rightsAcesso restrito
dc.titleCooperative activation of TLR2 and bradykinin B-2 receptor is required for induction of type 1 immunity in a mouse model of subcutaneous infection by Trypanosoma cruzien