Mitochondrial DNA activates the nlrP3 inflammasome and predisposes to Type 1 diabetes in murine model

Detalhes bibliográficos
Autor(a) principal: Carlos, Daniela
Data de Publicação: 2017
Outros Autores: 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.
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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spelling 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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