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Bradykinin B(2) Receptors of Dendritic Cells, Acting as Sensors of Kinins Proteolytically Released by Trypanosoma cruzi, Are Critical for the Development of Protective Type-1 Responses
Although the concept that dendritic cells (DCs) recognize pathogens through the engagement of Toll-like receptors is widely accepted, we recently suggested that immature DCs might sense kinin-releasing strains of Trypanosoma cruzi through the triggering of G-protein-coupled bradykinin B(2) receptors...
Autores principales: | , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2007
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2098834/ https://www.ncbi.nlm.nih.gov/pubmed/18052532 http://dx.doi.org/10.1371/journal.ppat.0030185 |
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author | Monteiro, Ana Carolina Schmitz, Verônica Morrot, Alexandre de Arruda, Luciana Barros Nagajyothi, Fnu Granato, Alessandra Pesquero, João B Müller-Esterl, Werner Tanowitz, Herbert B Scharfstein, Julio |
author_facet | Monteiro, Ana Carolina Schmitz, Verônica Morrot, Alexandre de Arruda, Luciana Barros Nagajyothi, Fnu Granato, Alessandra Pesquero, João B Müller-Esterl, Werner Tanowitz, Herbert B Scharfstein, Julio |
author_sort | Monteiro, Ana Carolina |
collection | PubMed |
description | Although the concept that dendritic cells (DCs) recognize pathogens through the engagement of Toll-like receptors is widely accepted, we recently suggested that immature DCs might sense kinin-releasing strains of Trypanosoma cruzi through the triggering of G-protein-coupled bradykinin B(2) receptors (B(2)R). Here we report that C57BL/6.B(2)R(−/−) mice infected intraperitoneally with T. cruzi display higher parasitemia and mortality rates as compared to B(2)R(+/+) mice. qRT-PCR revealed a 5-fold increase in T. cruzi DNA (14 d post-infection [p.i.]) in B(2)R(−/−) heart, while spleen parasitism was negligible in both mice strains. Analysis of recall responses (14 d p.i.) showed high and comparable frequencies of IFN-γ-producing CD4(+) and CD8(+) T cells in the spleen of B(2)R(−/−) and wild-type mice. However, production of IFN-γ by effector T cells isolated from B(2)R(−/−) heart was significantly reduced as compared with wild-type mice. As the infection continued, wild-type mice presented IFN-γ-producing (CD4(+)CD44(+) and CD8(+)CD44(+)) T cells both in the spleen and heart while B(2)R(−/−) mice showed negligible frequencies of such activated T cells. Furthermore, the collapse of type-1 immune responses in B(2)R(−/−) mice was linked to upregulated secretion of IL-17 and TNF-α by antigen-responsive CD4(+) T cells. In vitro analysis of tissue culture trypomastigote interaction with splenic CD11c(+) DCs indicated that DC maturation (IL-12, CD40, and CD86) is controlled by the kinin/B(2)R pathway. Further, systemic injection of trypomastigotes induced IL-12 production by CD11c(+) DCs isolated from B(2)R(+/+) spleen, but not by DCs from B(2)R(−/−) mice. Notably, adoptive transfer of B(2)R(+/+) CD11c(+) DCs (intravenously) into B(2)R(−/−) mice rendered them resistant to acute challenge, rescued development of type-1 immunity, and repressed T(H)17 responses. Collectively, our results demonstrate that activation of B(2)R, a DC sensor of endogenous maturation signals, is critically required for development of acquired resistance to T. cruzi infection. |
format | Text |
id | pubmed-2098834 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2007 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-20988342007-11-29 Bradykinin B(2) Receptors of Dendritic Cells, Acting as Sensors of Kinins Proteolytically Released by Trypanosoma cruzi, Are Critical for the Development of Protective Type-1 Responses Monteiro, Ana Carolina Schmitz, Verônica Morrot, Alexandre de Arruda, Luciana Barros Nagajyothi, Fnu Granato, Alessandra Pesquero, João B Müller-Esterl, Werner Tanowitz, Herbert B Scharfstein, Julio PLoS Pathog Research Article Although the concept that dendritic cells (DCs) recognize pathogens through the engagement of Toll-like receptors is widely accepted, we recently suggested that immature DCs might sense kinin-releasing strains of Trypanosoma cruzi through the triggering of G-protein-coupled bradykinin B(2) receptors (B(2)R). Here we report that C57BL/6.B(2)R(−/−) mice infected intraperitoneally with T. cruzi display higher parasitemia and mortality rates as compared to B(2)R(+/+) mice. qRT-PCR revealed a 5-fold increase in T. cruzi DNA (14 d post-infection [p.i.]) in B(2)R(−/−) heart, while spleen parasitism was negligible in both mice strains. Analysis of recall responses (14 d p.i.) showed high and comparable frequencies of IFN-γ-producing CD4(+) and CD8(+) T cells in the spleen of B(2)R(−/−) and wild-type mice. However, production of IFN-γ by effector T cells isolated from B(2)R(−/−) heart was significantly reduced as compared with wild-type mice. As the infection continued, wild-type mice presented IFN-γ-producing (CD4(+)CD44(+) and CD8(+)CD44(+)) T cells both in the spleen and heart while B(2)R(−/−) mice showed negligible frequencies of such activated T cells. Furthermore, the collapse of type-1 immune responses in B(2)R(−/−) mice was linked to upregulated secretion of IL-17 and TNF-α by antigen-responsive CD4(+) T cells. In vitro analysis of tissue culture trypomastigote interaction with splenic CD11c(+) DCs indicated that DC maturation (IL-12, CD40, and CD86) is controlled by the kinin/B(2)R pathway. Further, systemic injection of trypomastigotes induced IL-12 production by CD11c(+) DCs isolated from B(2)R(+/+) spleen, but not by DCs from B(2)R(−/−) mice. Notably, adoptive transfer of B(2)R(+/+) CD11c(+) DCs (intravenously) into B(2)R(−/−) mice rendered them resistant to acute challenge, rescued development of type-1 immunity, and repressed T(H)17 responses. Collectively, our results demonstrate that activation of B(2)R, a DC sensor of endogenous maturation signals, is critically required for development of acquired resistance to T. cruzi infection. Public Library of Science 2007-11 2007-11-30 /pmc/articles/PMC2098834/ /pubmed/18052532 http://dx.doi.org/10.1371/journal.ppat.0030185 Text en This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
spellingShingle | Research Article Monteiro, Ana Carolina Schmitz, Verônica Morrot, Alexandre de Arruda, Luciana Barros Nagajyothi, Fnu Granato, Alessandra Pesquero, João B Müller-Esterl, Werner Tanowitz, Herbert B Scharfstein, Julio Bradykinin B(2) Receptors of Dendritic Cells, Acting as Sensors of Kinins Proteolytically Released by Trypanosoma cruzi, Are Critical for the Development of Protective Type-1 Responses |
title | Bradykinin B(2) Receptors of Dendritic Cells, Acting as Sensors of Kinins Proteolytically Released by Trypanosoma cruzi, Are Critical for the Development of Protective Type-1 Responses |
title_full | Bradykinin B(2) Receptors of Dendritic Cells, Acting as Sensors of Kinins Proteolytically Released by Trypanosoma cruzi, Are Critical for the Development of Protective Type-1 Responses |
title_fullStr | Bradykinin B(2) Receptors of Dendritic Cells, Acting as Sensors of Kinins Proteolytically Released by Trypanosoma cruzi, Are Critical for the Development of Protective Type-1 Responses |
title_full_unstemmed | Bradykinin B(2) Receptors of Dendritic Cells, Acting as Sensors of Kinins Proteolytically Released by Trypanosoma cruzi, Are Critical for the Development of Protective Type-1 Responses |
title_short | Bradykinin B(2) Receptors of Dendritic Cells, Acting as Sensors of Kinins Proteolytically Released by Trypanosoma cruzi, Are Critical for the Development of Protective Type-1 Responses |
title_sort | bradykinin b(2) receptors of dendritic cells, acting as sensors of kinins proteolytically released by trypanosoma cruzi, are critical for the development of protective type-1 responses |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2098834/ https://www.ncbi.nlm.nih.gov/pubmed/18052532 http://dx.doi.org/10.1371/journal.ppat.0030185 |
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