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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Mitochondrial Dna activates the nlrP3 inflammasome and Predisposes to Type 1 Diabetes in Murine Model

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Carlos, Daniela ; Costa, Frederico R. C. ; Pereira, Camila A. ; Rocha, Fernanda A. ; Yaochite, Juliana N. U. ; Oliveira, Gabriela G. ; Carneiro, Fernando S. ; Tostes, Rita C. ; Ramos, Simone G. ; Zamboni, Dario S. ; Camara, Niels O. S. ; Ryffel, Bernhard ; Silva, Joao S.
Total Authors: 13
Document type: Journal article
Source: FRONTIERS IN IMMUNOLOGY; v. 8, FEB 25 2017.
Web of Science Citations: 18
Abstract

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-1 beta gene expression in pancreatic lymph nodes (PLNs). Similar increases in gene expression of NLRP3, apoptosis associated speck like protein (ASC) and pro-IL-1 beta were induced by multiple low doses of streptozotocin (STZ) in C57BL/6 mice. In addition, diabetic C57BL/6 mice also exhibited increased IL-1 beta 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-gamma-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-1 beta 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-1 beta production and contributes to pathogenic cellular responses during the development of STZ-induced T1D. (AU)

FAPESP's process: 12/10395-0 - Role of NLRs receptors in immunoregulation mechanisms of the type 1 and 2 diabetes: identification of potential therapeutic targets
Grantee:Daniela Carlos Sartori
Support Opportunities: Research Grants - Young Investigators Grants
FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
Grantee:Fernando de Queiroz Cunha
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC