Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/10103
Title: C5a and Bradykinin Receptor Cross-Talk Regulates Innate and Adaptive Immunity in Trypanosoma cruzi Infection
Authors: Schmitz, Veronica
Almeida, Larissa Nogueira
Svensjö, Erik
Monteiro, Ana Carolina
Köhl, Jörg
Scharfstein, Julio
Affilliation: Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil.
University of Lübeck. Institute for Systemic Inflammation Research. Lübeck, Germany / University of Cincinnati. College of Medicine. Cincinnati Children’s Hospital Medical Center. Division of Immunobiology. Cincinnati, OH, USA.
Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil.
Abstract: Complement and the kallikrein–kinin cascade system are both activated in injured tissues. Little is known about their partnership in the immunopathogenesis of Chagas disease, the chronic infection caused by the intracellular protozoan Trypanosoma cruzi. In this study, we show that pharmacological targeting of the C5a receptor (C5aR) or the bradykinin B2 receptor (B2R) inhibited plasma leakage in hamster cheek pouch topically exposed to tissue culture trypomastigotes (TCTs). Further, angiotensin-converting enzyme inhibitors potentiated TCT-evoked paw edema in BALB/c, C57BL/6, and C5-deficient A/J mice through activation of joint pathways between C5aR/B2R or C3aR/B2R. In addition to generation of C5a and kinins via parasite-derived cruzipain, we demonstrate that macrophages internalize TCTs more efficiently through joint activation of C5aR/B2R. Furthermore, we found that C5aR targeting markedly reduces NO production and intracellular parasitism in macrophages. We then studied the impact of C5aR/B2R cross-talk in TCT infection on the development of adaptive immunity. We found that IL-12p40/70 expression was blunted in splenic dendritic cells by blocking either C5aR or B2R, suggesting that codominant signaling via C5aR and B2R fuels production of the Th1-polarizing cytokine. Finally, we assessed the impact of kinins and C5a liberated in parasite-laden tissues on Th cell differentiation. As predicted, BALB/c mice pretreated with angiotensin-converting enzyme inhibitors potentiated IFN-γ production by Ag-specific T cells via C5aR/B2R cross-talk. Interestingly, we found that B2R targeting upregulated IL-10 secretion, whereas C5aR blockade vigorously stimulated IL-4 production. In summary, we describe a novel pathway by which C5aR/B2R cross-talk couples transendothelial leakage of plasma proteins to the cytokine circuitry that coordinates antiparasite immunity.
Keywords: Trypanosoma cruzi
Chagas Disease
keywords: Doença de Chagas
Trypanosma cruzi
Issue Date: 2014
Publisher: The American Association of Immunologists
Citation: SCHMITZ, Veronica et al. C5a and Bradykinin Receptor Cross-Talk Regulates Innate and Adaptive Immunity in Trypanosoma cruzi Infection. The Journal of Immunology, v.193, n.7, p.3613-3623, 2014.
DOI: 10.4049/jimmunol.1302417
ISSN: 1550-6606
Copyright: restricted access
Appears in Collections:IOC - Artigos de Periódicos

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