The Kallikrein-Kinin-System in Experimental Chagas Disease: A Paradigm to Investigate the Impact of Inflammatory Edema on GPCR-mediated pathways of Host Cell Invasion by Trypanosoma cruzi
Chronic chagasic myocarditis (CCM) depends on Trypanosoma cruzi persistence in the myocardium. Studies of the proteolytic mechanisms governing host/parasite balance in peripheral sites of T. cruzi infection revealed that tissue culture trypomastigotes (TCTs) elicit inflammatory edema and stimulate p...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2013-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fimmu.2012.00396/full |
| _version_ | 1811213160974123008 |
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| author | Julio eScharfstein Daniele eAndrade Erik eSvensjö Ana Carolina eOliveira Clarissa Rodrigues Nascimento |
| author_facet | Julio eScharfstein Daniele eAndrade Erik eSvensjö Ana Carolina eOliveira Clarissa Rodrigues Nascimento |
| author_sort | Julio eScharfstein |
| collection | DOAJ |
| description | Chronic chagasic myocarditis (CCM) depends on Trypanosoma cruzi persistence in the myocardium. Studies of the proteolytic mechanisms governing host/parasite balance in peripheral sites of T. cruzi infection revealed that tissue culture trypomastigotes (TCTs) elicit inflammatory edema and stimulate protective type-1 effector T cells through the activation of the Kallikrein-Kinin System (KKS). Molecular studies linked the proinflammatory phenotype of Dm28c TCTs to the synergistic activities of tGPI, a lipid anchor that functions as a TLR2 ligand, and cruzipain, a kinin-releasing cysteine protease. Analysis of the dynamics of inflammation revealed that TCTs activate innate sentinel cells via TLR2, releasing CXC chemokines, which in turn evoke neutrophil/CXCR2-dependent extravasation of plasma proteins, including high molecular weight kininogen (HK), in parasite-laden tissues. Further downstream, TCTs process surface bound HK, liberating lysyl-BK (LBK), which then propagates inflammatory edema via signaling of endothelial G-protein-coupled bradykinin B2 receptors (BK2R). Dm28 TCTs take advantage of the transient availability of infection-promoting peptides (e.g., bradykinin and endothelins) in inflamed tissues to invade cardiovascular cells via interdependent signaling of BKRs and endothelin receptors (ETRs). Herein we present a space-filling model whereby ceramide-enriched endocytic vesicles generated by the shingomyelinase pathway might incorporate BK2R and ETRs, which then trigger Ca2+-driven responses that optimize the housekeeping mechanism of plasma membrane repair from cell wounding. The hypothesis predicts that the NFB-inducible BKR (BK1R) may integrate the multimolecular signaling platforms forged by ceramide rafts, as the chronic myocarditis progresses. Exploited as gateways for parasite invasion, BK2R, BK1R, ETAR, ETBR and other GPCR partners may enable persistent myocardial parasitism in the edematous tissues at expense of adverse cardiac remodelling. |
| first_indexed | 2024-04-12T05:42:12Z |
| format | Article |
| id | doaj.art-64eb84e57a264886ba72b5a4dff06251 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T05:42:12Z |
| publishDate | 2013-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-64eb84e57a264886ba72b5a4dff062512022-12-22T03:45:36ZengFrontiers Media S.A.Frontiers in Immunology1664-32242013-01-01310.3389/fimmu.2012.0039636566The Kallikrein-Kinin-System in Experimental Chagas Disease: A Paradigm to Investigate the Impact of Inflammatory Edema on GPCR-mediated pathways of Host Cell Invasion by Trypanosoma cruziJulio eScharfstein0Daniele eAndrade1Erik eSvensjö2Ana Carolina eOliveira3Clarissa Rodrigues Nascimento4Universidade Federal do Rio de JaneiroUniversidade Federal do Rio de JaneiroUniversidade Federal do Rio de JaneiroUniversidade Federal do Rio de JaneiroUniversidade Federal do Rio de JaneiroChronic chagasic myocarditis (CCM) depends on Trypanosoma cruzi persistence in the myocardium. Studies of the proteolytic mechanisms governing host/parasite balance in peripheral sites of T. cruzi infection revealed that tissue culture trypomastigotes (TCTs) elicit inflammatory edema and stimulate protective type-1 effector T cells through the activation of the Kallikrein-Kinin System (KKS). Molecular studies linked the proinflammatory phenotype of Dm28c TCTs to the synergistic activities of tGPI, a lipid anchor that functions as a TLR2 ligand, and cruzipain, a kinin-releasing cysteine protease. Analysis of the dynamics of inflammation revealed that TCTs activate innate sentinel cells via TLR2, releasing CXC chemokines, which in turn evoke neutrophil/CXCR2-dependent extravasation of plasma proteins, including high molecular weight kininogen (HK), in parasite-laden tissues. Further downstream, TCTs process surface bound HK, liberating lysyl-BK (LBK), which then propagates inflammatory edema via signaling of endothelial G-protein-coupled bradykinin B2 receptors (BK2R). Dm28 TCTs take advantage of the transient availability of infection-promoting peptides (e.g., bradykinin and endothelins) in inflamed tissues to invade cardiovascular cells via interdependent signaling of BKRs and endothelin receptors (ETRs). Herein we present a space-filling model whereby ceramide-enriched endocytic vesicles generated by the shingomyelinase pathway might incorporate BK2R and ETRs, which then trigger Ca2+-driven responses that optimize the housekeeping mechanism of plasma membrane repair from cell wounding. The hypothesis predicts that the NFB-inducible BKR (BK1R) may integrate the multimolecular signaling platforms forged by ceramide rafts, as the chronic myocarditis progresses. Exploited as gateways for parasite invasion, BK2R, BK1R, ETAR, ETBR and other GPCR partners may enable persistent myocardial parasitism in the edematous tissues at expense of adverse cardiac remodelling.http://journal.frontiersin.org/Journal/10.3389/fimmu.2012.00396/fullBradykininEndothelinsTrypanosoma cruziGPCRscardiomyopathyProteases |
| spellingShingle | Julio eScharfstein Daniele eAndrade Erik eSvensjö Ana Carolina eOliveira Clarissa Rodrigues Nascimento The Kallikrein-Kinin-System in Experimental Chagas Disease: A Paradigm to Investigate the Impact of Inflammatory Edema on GPCR-mediated pathways of Host Cell Invasion by Trypanosoma cruzi Frontiers in Immunology Bradykinin Endothelins Trypanosoma cruzi GPCRs cardiomyopathy Proteases |
| title | The Kallikrein-Kinin-System in Experimental Chagas Disease: A Paradigm to Investigate the Impact of Inflammatory Edema on GPCR-mediated pathways of Host Cell Invasion by Trypanosoma cruzi |
| title_full | The Kallikrein-Kinin-System in Experimental Chagas Disease: A Paradigm to Investigate the Impact of Inflammatory Edema on GPCR-mediated pathways of Host Cell Invasion by Trypanosoma cruzi |
| title_fullStr | The Kallikrein-Kinin-System in Experimental Chagas Disease: A Paradigm to Investigate the Impact of Inflammatory Edema on GPCR-mediated pathways of Host Cell Invasion by Trypanosoma cruzi |
| title_full_unstemmed | The Kallikrein-Kinin-System in Experimental Chagas Disease: A Paradigm to Investigate the Impact of Inflammatory Edema on GPCR-mediated pathways of Host Cell Invasion by Trypanosoma cruzi |
| title_short | The Kallikrein-Kinin-System in Experimental Chagas Disease: A Paradigm to Investigate the Impact of Inflammatory Edema on GPCR-mediated pathways of Host Cell Invasion by Trypanosoma cruzi |
| title_sort | kallikrein kinin system in experimental chagas disease a paradigm to investigate the impact of inflammatory edema on gpcr mediated pathways of host cell invasion by trypanosoma cruzi |
| topic | Bradykinin Endothelins Trypanosoma cruzi GPCRs cardiomyopathy Proteases |
| url | http://journal.frontiersin.org/Journal/10.3389/fimmu.2012.00396/full |
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