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.

• 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