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NLRP3 Controls Trypanosoma cruzi Infection through a Caspase-1-Dependent IL-1R-Independent NO Production
Trypanosoma cruzi (T. cruzi) is an intracellular protozoan parasite and the etiological agent of Chagas disease, a chronic infectious illness that affects millions of people worldwide. Although the role of TLR and Nod1 in the control of T. cruzi infection is well-established, the involvement of infl...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789781/ https://www.ncbi.nlm.nih.gov/pubmed/24098823 http://dx.doi.org/10.1371/journal.pntd.0002469 |
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author | Gonçalves, Virginia M. Matteucci, Kely C. Buzzo, Carina L. Miollo, Bruna H. Ferrante, Danny Torrecilhas, Ana C. Rodrigues, Mauricio M. Alvarez, Jose M. Bortoluci, Karina R. |
author_facet | Gonçalves, Virginia M. Matteucci, Kely C. Buzzo, Carina L. Miollo, Bruna H. Ferrante, Danny Torrecilhas, Ana C. Rodrigues, Mauricio M. Alvarez, Jose M. Bortoluci, Karina R. |
author_sort | Gonçalves, Virginia M. |
collection | PubMed |
description | Trypanosoma cruzi (T. cruzi) is an intracellular protozoan parasite and the etiological agent of Chagas disease, a chronic infectious illness that affects millions of people worldwide. Although the role of TLR and Nod1 in the control of T. cruzi infection is well-established, the involvement of inflammasomes remains to be elucidated. Herein, we demonstrate for the first time that T. cruzi infection induces IL-1β production in an NLRP3- and caspase-1-dependent manner. Cathepsin B appears to be required for NLRP3 activation in response to infection with T. cruzi, as pharmacological inhibition of cathepsin B abrogates IL-1β secretion. NLRP3(−/−) and caspase1(−/−) mice exhibited high numbers of T. cruzi parasites, with a magnitude of peak parasitemia comparable to MyD88(−/−) and iNOS(−/−) mice (which are susceptible models for T. cruzi infection), indicating the involvement of NLRP3 inflammasome in the control of the acute phase of T. cruzi infection. Although the inflammatory cytokines IL-6 and IFN-γ were found in spleen cells from NLRP3(−/−) and caspase1(−/−) mice infected with T. cruzi, these mice exhibited severe defects in nitric oxide (NO) production and an impairment in macrophage-mediated parasite killing. Interestingly, neutralization of IL-1β and IL-18, and IL-1R genetic deficiency demonstrate that these cytokines have a minor effect on NO secretion and the capacity of macrophages to control T. cruzi infection. In contrast, inhibition of caspase-1 with z-YVAD-fmk abrogated NO production by WT and MyD88(−/−) macrophages and rendered them as susceptible to T. cruzi infection as NLRP3(−/−) and caspase-1(−/−) macrophages. Taken together, our results demonstrate a role for the NLRP3 inflammasome in the control of T. cruzi infection and identify NLRP3-mediated, caspase-1-dependent and IL-1R-independent NO production as a novel effector mechanism for these innate receptors. |
format | Online Article Text |
id | pubmed-3789781 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-37897812013-10-04 NLRP3 Controls Trypanosoma cruzi Infection through a Caspase-1-Dependent IL-1R-Independent NO Production Gonçalves, Virginia M. Matteucci, Kely C. Buzzo, Carina L. Miollo, Bruna H. Ferrante, Danny Torrecilhas, Ana C. Rodrigues, Mauricio M. Alvarez, Jose M. Bortoluci, Karina R. PLoS Negl Trop Dis Research Article Trypanosoma cruzi (T. cruzi) is an intracellular protozoan parasite and the etiological agent of Chagas disease, a chronic infectious illness that affects millions of people worldwide. Although the role of TLR and Nod1 in the control of T. cruzi infection is well-established, the involvement of inflammasomes remains to be elucidated. Herein, we demonstrate for the first time that T. cruzi infection induces IL-1β production in an NLRP3- and caspase-1-dependent manner. Cathepsin B appears to be required for NLRP3 activation in response to infection with T. cruzi, as pharmacological inhibition of cathepsin B abrogates IL-1β secretion. NLRP3(−/−) and caspase1(−/−) mice exhibited high numbers of T. cruzi parasites, with a magnitude of peak parasitemia comparable to MyD88(−/−) and iNOS(−/−) mice (which are susceptible models for T. cruzi infection), indicating the involvement of NLRP3 inflammasome in the control of the acute phase of T. cruzi infection. Although the inflammatory cytokines IL-6 and IFN-γ were found in spleen cells from NLRP3(−/−) and caspase1(−/−) mice infected with T. cruzi, these mice exhibited severe defects in nitric oxide (NO) production and an impairment in macrophage-mediated parasite killing. Interestingly, neutralization of IL-1β and IL-18, and IL-1R genetic deficiency demonstrate that these cytokines have a minor effect on NO secretion and the capacity of macrophages to control T. cruzi infection. In contrast, inhibition of caspase-1 with z-YVAD-fmk abrogated NO production by WT and MyD88(−/−) macrophages and rendered them as susceptible to T. cruzi infection as NLRP3(−/−) and caspase-1(−/−) macrophages. Taken together, our results demonstrate a role for the NLRP3 inflammasome in the control of T. cruzi infection and identify NLRP3-mediated, caspase-1-dependent and IL-1R-independent NO production as a novel effector mechanism for these innate receptors. Public Library of Science 2013-10-03 /pmc/articles/PMC3789781/ /pubmed/24098823 http://dx.doi.org/10.1371/journal.pntd.0002469 Text en © 2013 Gonçalves et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Gonçalves, Virginia M. Matteucci, Kely C. Buzzo, Carina L. Miollo, Bruna H. Ferrante, Danny Torrecilhas, Ana C. Rodrigues, Mauricio M. Alvarez, Jose M. Bortoluci, Karina R. NLRP3 Controls Trypanosoma cruzi Infection through a Caspase-1-Dependent IL-1R-Independent NO Production |
title | NLRP3 Controls Trypanosoma cruzi Infection through a Caspase-1-Dependent IL-1R-Independent NO Production |
title_full | NLRP3 Controls Trypanosoma cruzi Infection through a Caspase-1-Dependent IL-1R-Independent NO Production |
title_fullStr | NLRP3 Controls Trypanosoma cruzi Infection through a Caspase-1-Dependent IL-1R-Independent NO Production |
title_full_unstemmed | NLRP3 Controls Trypanosoma cruzi Infection through a Caspase-1-Dependent IL-1R-Independent NO Production |
title_short | NLRP3 Controls Trypanosoma cruzi Infection through a Caspase-1-Dependent IL-1R-Independent NO Production |
title_sort | nlrp3 controls trypanosoma cruzi infection through a caspase-1-dependent il-1r-independent no production |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789781/ https://www.ncbi.nlm.nih.gov/pubmed/24098823 http://dx.doi.org/10.1371/journal.pntd.0002469 |
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