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Mitochondrial DNA Activates the NLRP3 Inflammasome and Predisposes to Type 1
Diabetes in Murine Model
#MMPMID28289409
Carlos D
; Costa FR
; Pereira CA
; Rocha FA
; Yaochite JN
; Oliveira GG
; Carneiro FS
; Tostes RC
; Ramos SG
; Zamboni DS
; Camara NO
; Ryffel B
; Silva JS
Front Immunol
2017[]; 8
(?): 164
PMID28289409
show ga
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? gene expression in pancreatic lymph
nodes (PLNs). Similar increases in gene expression of NLRP3, apoptosis associated
speck like protein (ASC) and pro-IL-1? were induced by multiple low doses of
streptozotocin (STZ) in C57BL/6 mice. In addition, diabetic C57BL/6 mice also
exhibited increased IL-1? 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-?-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? 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? production and contributes to pathogenic cellular
responses during the development of STZ-induced T1D.
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