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

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

Author Monteiro, Ana Carolina Google Scholar
Schmitz, Veronica Google Scholar
Svensjo, Erik Google Scholar
Gazzinelli, Ricardo T. Google Scholar
Almeida, Igor C. Google Scholar
Todorov, Alex Google Scholar
Arruda, Luciana B. de Google Scholar
Torrecilhas, Ana Claudia T. Google Scholar
Pesquero, Joao B. Autor UNIFESP Google Scholar
Morrot, Alexandre Google Scholar
Bouskela, Eliete Google Scholar
Bonomo, Adriana Google Scholar
Lima, Ana Paula C. A. Google Scholar
Mueller-Esterl, Werner Google Scholar
Scharfstein, Julio Google Scholar
Institution Universidade Federal do Rio de Janeiro (UFRJ)
Ctr Pesquisas Rene Rachou Fiocruz
Universidade Federal de Minas Gerais (UFMG)
Univ Texas
Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
Johns Hopkins Univ
Universidade do Estado do Rio de Janeiro (UERJ)
Univ Frankfurt
Abstract We 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.
Language English
Date 2006-11-01
Published in Journal Of Immunology. Bethesda: Amer Assoc Immunologists, v. 177, n. 9, p. 6325-6335, 2006.
ISSN 0022-1767 (Sherpa/Romeo, impact factor)
Publisher Amer Assoc Immunologists
Extent 6325-6335
Access rights Closed access
Type Article
Web of Science ID WOS:000241477400067

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