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* Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil;
Laboratório de Imunopatologia, Centro de Pesquisas René Rachou-Fiocruz, Belo Horizonte, Brazil;
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil;
Department of Biological Sciences, University of Texas, El Paso, TX 79968;
¶ Instituto de Microbiologia, UFRJ, Rio de Janeiro, Brazil;
|| Departamento de Bioquimica, Universidade de São Paulo, São Paulo, Brazil;
# Departmento de Biofisica, Universidade Federal de São Paulo, São Paulo, Brazil;
** Department of Molecular Microbiology and Immunology, Johns Hopkins University, Baltimore, MD 21205;
Laboratório de Microcirculação, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil; and
* Institute of Biochemistry II, University of Frankfurt Medical School, Frankfurt, Germany
We have previously reported that exogenous bradykinin activates immature dendritic cells (DCs) via the bradykinin B2 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-
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 extravasation, 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 1 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 1 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was funded by World Health Organization-Special Program for Research and Training in Tropical Diseases (IDA10340), Wellcome Trust (072349/Z/03/Z), Conselho Nacional de Pesquisas, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, Comissao de Aperfeiçoamento de Pessoal de Nival Superior, Fundaçao de Amparo à Pesquisa do Estado de Minas Gerais, and Fundaçao de Amparo à Pesquisa do Estado de Sao Paulo, Volkswagen Stiftung and Fonds der Chemischen Industrie. I.C.A. was supported by a National Institutes of Health Grant (5G12RR008124) to Border Biomedical Research Center/Biology/University of Texas El Paso. A.C.M. received a fellowship from the Tuberculosis Research Network/Conselho Nacional de Pesquisus.
2 Address correspondence and reprint requests to Dr. Julio Scharfstein, Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Instituto de Biofisica Carlos Chagas Filho, Laboratório de Imunologia Molecular, Bloco D. Sala D 007, Rio de Janeiro, Brazil. E-mail address: scharf{at}biof.ufrj.br
3 Abbreviations used in this paper: BK, bradykinin; HK, high m.w. kininogen; BR, BK receptor; DC, dendritic cell; ACE, angiotensin converting enzyme; ACEi, ACE inhibitor; TCT, tissue culture trypomastigote; LN, lymph node; NMS, normal mouse serum; tGPI-m, trypomastigote-derived GPI-anchored mucin; VSPh, methylpiperazine-Phe-homoPhe-vinylsulfone-benzene; PMN, polymorphonuclear neutrophil; WT, wild type; PAMP, pathogen-associated molecular pattern; LBK, lysyl-BK.
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