Mitochondrial DNA activates the nlrP3 inflammasome and predisposes to Type 1 diabetes in murine model
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Outros Autores: | , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da Universidade Federal do Ceará (UFC) |
Texto Completo: | http://www.repositorio.ufc.br/handle/riufc/40347 |
Resumo: | Although a correlation between polymorphisms of NOD-like receptor family-pyrin domain containing 3 (NLRP3) and predisposition to type 1 diabetes (T1D) has been identified, the potential function and activation of the NLRP3 inflammasome in T1D have not been clarified. The present study shows that non-obese diabetic mice exhibited increased NLRP3, and pro-IL-1β gene expression in pancreatic lymph nodes (PLNs). Similar increases in gene expression of NLRP3, apoptosis associated speck like protein (ASC) and pro-IL-1β were induced by multiple low doses of streptozotocin (STZ) in C57BL/6 mice. In addition, diabetic C57BL/6 mice also exhibited increased IL-1β protein expression in the pancreatic tissue at day 7, which remained elevated until day 15. Diabetic mice also showed increased positive caspase-1 macrophages in the PLNs, which were decreased in NLRP3−/− mice, but not in ASC−/− mice, after STZ treatment. NLRP3- and IL-1R-deficient mice, but not ASC-deficient mice, showed reduced incidence of diabetes, less insulitis, lower hyperglycemia, and normal insulin levels compared to wild-type (WT) diabetic mice. Notably, these mice also displayed a decrease in IL-17-producing CD4 and CD8 T cells (Th17 and Tc17) and IFN-γ-producing CD4 and CD8 T cells (Th1 and Tc1) in the PLNs. Following STZ treatment to induce T1D, NLRP3-deficient mice also exhibited an increase in myeloid-derived suppressor cell and mast cell numbers in the PLNs along with a significant increase in IL-6, IL-10, and IL-4 expression in the pancreatic tissue. Interestingly, diabetic mice revealed increased circulating expression of genes related to mitochondrial DNA, such as cytochrome b and cytochrome c, but not NADH dehydrogenase subunit 6 (NADH). Mitochondrial DNA (mDNA) from diabetic mice, but not from non-diabetic mice, induced significant IL-1β production and caspase-1 activation by WT macrophages, which was reduced in NLRP3−/− macrophages. Finally, mDNA administration in vivo increased Th17/Tc17/Th1/Tc1 cells in the PLNs and precipitated T1D onset, which was abolished in NLRP3−/− mice. Overall, our results demonstrate that mDNA-mediated NLRP3 activation triggers caspase-1- dependent IL-1β production and contributes to pathogenic cellular responses during the development of STZ-induced T1D. |
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Repositório Institucional da Universidade Federal do Ceará (UFC) |
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Mitochondrial DNA activates the nlrP3 inflammasome and predisposes to Type 1 diabetes in murine modelDiabetes MellitusDNA MitocondrialAlthough a correlation between polymorphisms of NOD-like receptor family-pyrin domain containing 3 (NLRP3) and predisposition to type 1 diabetes (T1D) has been identified, the potential function and activation of the NLRP3 inflammasome in T1D have not been clarified. The present study shows that non-obese diabetic mice exhibited increased NLRP3, and pro-IL-1β gene expression in pancreatic lymph nodes (PLNs). Similar increases in gene expression of NLRP3, apoptosis associated speck like protein (ASC) and pro-IL-1β were induced by multiple low doses of streptozotocin (STZ) in C57BL/6 mice. In addition, diabetic C57BL/6 mice also exhibited increased IL-1β protein expression in the pancreatic tissue at day 7, which remained elevated until day 15. Diabetic mice also showed increased positive caspase-1 macrophages in the PLNs, which were decreased in NLRP3−/− mice, but not in ASC−/− mice, after STZ treatment. NLRP3- and IL-1R-deficient mice, but not ASC-deficient mice, showed reduced incidence of diabetes, less insulitis, lower hyperglycemia, and normal insulin levels compared to wild-type (WT) diabetic mice. Notably, these mice also displayed a decrease in IL-17-producing CD4 and CD8 T cells (Th17 and Tc17) and IFN-γ-producing CD4 and CD8 T cells (Th1 and Tc1) in the PLNs. Following STZ treatment to induce T1D, NLRP3-deficient mice also exhibited an increase in myeloid-derived suppressor cell and mast cell numbers in the PLNs along with a significant increase in IL-6, IL-10, and IL-4 expression in the pancreatic tissue. Interestingly, diabetic mice revealed increased circulating expression of genes related to mitochondrial DNA, such as cytochrome b and cytochrome c, but not NADH dehydrogenase subunit 6 (NADH). Mitochondrial DNA (mDNA) from diabetic mice, but not from non-diabetic mice, induced significant IL-1β production and caspase-1 activation by WT macrophages, which was reduced in NLRP3−/− macrophages. Finally, mDNA administration in vivo increased Th17/Tc17/Th1/Tc1 cells in the PLNs and precipitated T1D onset, which was abolished in NLRP3−/− mice. Overall, our results demonstrate that mDNA-mediated NLRP3 activation triggers caspase-1- dependent IL-1β production and contributes to pathogenic cellular responses during the development of STZ-induced T1D.Frontiers in Immunology2019-03-20T13:58:43Z2019-03-20T13:58:43Z2017-02info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfCARLOS, Daniela et al. Mitochondrial DNA activates the nlrP3 inflammasome and predisposes to Type 1 diabetes in murine model. Frontiers in Immunology, v. 8, p. 1-18, feb. 2017.1664-3224 (On line)http://www.repositorio.ufc.br/handle/riufc/40347Carlos, DanielaCosta, Frederico R. C.Pereira, Camila A.Rocha, Fernanda A.Yaochite, Juliana Navarro UedaOliveira, Gabriela G.Carneiro, Fernando S.Tostes, Rita C.Ramos, Simone G.Zamboni, Dario S.Camara, Niels O. S.Ryffel, BernhardSilva, João S.engreponame:Repositório Institucional da Universidade Federal do Ceará (UFC)instname:Universidade Federal do Ceará (UFC)instacron:UFCinfo:eu-repo/semantics/openAccess2022-11-03T19:32:31Zoai:repositorio.ufc.br:riufc/40347Repositório InstitucionalPUBhttp://www.repositorio.ufc.br/ri-oai/requestbu@ufc.br || repositorio@ufc.bropendoar:2024-09-11T18:59:28.883593Repositório Institucional da Universidade Federal do Ceará (UFC) - Universidade Federal do Ceará (UFC)false |
dc.title.none.fl_str_mv |
Mitochondrial DNA activates the nlrP3 inflammasome and predisposes to Type 1 diabetes in murine model |
title |
Mitochondrial DNA activates the nlrP3 inflammasome and predisposes to Type 1 diabetes in murine model |
spellingShingle |
Mitochondrial DNA activates the nlrP3 inflammasome and predisposes to Type 1 diabetes in murine model Carlos, Daniela Diabetes Mellitus DNA Mitocondrial |
title_short |
Mitochondrial DNA activates the nlrP3 inflammasome and predisposes to Type 1 diabetes in murine model |
title_full |
Mitochondrial DNA activates the nlrP3 inflammasome and predisposes to Type 1 diabetes in murine model |
title_fullStr |
Mitochondrial DNA activates the nlrP3 inflammasome and predisposes to Type 1 diabetes in murine model |
title_full_unstemmed |
Mitochondrial DNA activates the nlrP3 inflammasome and predisposes to Type 1 diabetes in murine model |
title_sort |
Mitochondrial DNA activates the nlrP3 inflammasome and predisposes to Type 1 diabetes in murine model |
author |
Carlos, Daniela |
author_facet |
Carlos, Daniela Costa, Frederico R. C. Pereira, Camila A. Rocha, Fernanda A. Yaochite, Juliana Navarro Ueda Oliveira, Gabriela G. Carneiro, Fernando S. Tostes, Rita C. Ramos, Simone G. Zamboni, Dario S. Camara, Niels O. S. Ryffel, Bernhard Silva, João S. |
author_role |
author |
author2 |
Costa, Frederico R. C. Pereira, Camila A. Rocha, Fernanda A. Yaochite, Juliana Navarro Ueda Oliveira, Gabriela G. Carneiro, Fernando S. Tostes, Rita C. Ramos, Simone G. Zamboni, Dario S. Camara, Niels O. S. Ryffel, Bernhard Silva, João S. |
author2_role |
author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Carlos, Daniela Costa, Frederico R. C. Pereira, Camila A. Rocha, Fernanda A. Yaochite, Juliana Navarro Ueda Oliveira, Gabriela G. Carneiro, Fernando S. Tostes, Rita C. Ramos, Simone G. Zamboni, Dario S. Camara, Niels O. S. Ryffel, Bernhard Silva, João S. |
dc.subject.por.fl_str_mv |
Diabetes Mellitus DNA Mitocondrial |
topic |
Diabetes Mellitus DNA Mitocondrial |
description |
Although a correlation between polymorphisms of NOD-like receptor family-pyrin domain containing 3 (NLRP3) and predisposition to type 1 diabetes (T1D) has been identified, the potential function and activation of the NLRP3 inflammasome in T1D have not been clarified. The present study shows that non-obese diabetic mice exhibited increased NLRP3, and pro-IL-1β gene expression in pancreatic lymph nodes (PLNs). Similar increases in gene expression of NLRP3, apoptosis associated speck like protein (ASC) and pro-IL-1β were induced by multiple low doses of streptozotocin (STZ) in C57BL/6 mice. In addition, diabetic C57BL/6 mice also exhibited increased IL-1β protein expression in the pancreatic tissue at day 7, which remained elevated until day 15. Diabetic mice also showed increased positive caspase-1 macrophages in the PLNs, which were decreased in NLRP3−/− mice, but not in ASC−/− mice, after STZ treatment. NLRP3- and IL-1R-deficient mice, but not ASC-deficient mice, showed reduced incidence of diabetes, less insulitis, lower hyperglycemia, and normal insulin levels compared to wild-type (WT) diabetic mice. Notably, these mice also displayed a decrease in IL-17-producing CD4 and CD8 T cells (Th17 and Tc17) and IFN-γ-producing CD4 and CD8 T cells (Th1 and Tc1) in the PLNs. Following STZ treatment to induce T1D, NLRP3-deficient mice also exhibited an increase in myeloid-derived suppressor cell and mast cell numbers in the PLNs along with a significant increase in IL-6, IL-10, and IL-4 expression in the pancreatic tissue. Interestingly, diabetic mice revealed increased circulating expression of genes related to mitochondrial DNA, such as cytochrome b and cytochrome c, but not NADH dehydrogenase subunit 6 (NADH). Mitochondrial DNA (mDNA) from diabetic mice, but not from non-diabetic mice, induced significant IL-1β production and caspase-1 activation by WT macrophages, which was reduced in NLRP3−/− macrophages. Finally, mDNA administration in vivo increased Th17/Tc17/Th1/Tc1 cells in the PLNs and precipitated T1D onset, which was abolished in NLRP3−/− mice. Overall, our results demonstrate that mDNA-mediated NLRP3 activation triggers caspase-1- dependent IL-1β production and contributes to pathogenic cellular responses during the development of STZ-induced T1D. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017-02 2019-03-20T13:58:43Z 2019-03-20T13:58:43Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
CARLOS, Daniela et al. Mitochondrial DNA activates the nlrP3 inflammasome and predisposes to Type 1 diabetes in murine model. Frontiers in Immunology, v. 8, p. 1-18, feb. 2017. 1664-3224 (On line) http://www.repositorio.ufc.br/handle/riufc/40347 |
identifier_str_mv |
CARLOS, Daniela et al. Mitochondrial DNA activates the nlrP3 inflammasome and predisposes to Type 1 diabetes in murine model. Frontiers in Immunology, v. 8, p. 1-18, feb. 2017. 1664-3224 (On line) |
url |
http://www.repositorio.ufc.br/handle/riufc/40347 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Frontiers in Immunology |
publisher.none.fl_str_mv |
Frontiers in Immunology |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da Universidade Federal do Ceará (UFC) instname:Universidade Federal do Ceará (UFC) instacron:UFC |
instname_str |
Universidade Federal do Ceará (UFC) |
instacron_str |
UFC |
institution |
UFC |
reponame_str |
Repositório Institucional da Universidade Federal do Ceará (UFC) |
collection |
Repositório Institucional da Universidade Federal do Ceará (UFC) |
repository.name.fl_str_mv |
Repositório Institucional da Universidade Federal do Ceará (UFC) - Universidade Federal do Ceará (UFC) |
repository.mail.fl_str_mv |
bu@ufc.br || repositorio@ufc.br |
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1813029024582074368 |