Abstract
Accumulation of advanced glycation end products (AGEs) contributes to ageing and age-related diseases, especially type 2 diabetes. The NLRP3 inflammasome, as a vital component of the innate immune system, is implicated in the pathogenesis of type 2 diabetes. However, the role of the NLRP3 inflammasome in AGE-induced pancreatic islet damage remains largely unclear. Results showed that administration of AGEs (120 mg/kg for 6 weeks) in C57BL/6J mice induced an abnormal response to glucose (as measured by glucose tolerance and insulin release), pancreatic β-cell ultrastructural lesion, and cell death. These effects were associated with an excessive superoxide anion level, significant increased protein expression levels for NADPH oxidase 2 (NOX2), thioredoxin-interacting protein (TXNIP), NLRP3, and cleaved IL-1β, enhanced caspase-1 activity, and a significant increase in the levels of TXNIP–NLRP3 protein interaction. Ablation of the NLRP3 inflammasome or treatment with antioxidant N-acetyl-cysteine (NAC) clearly ameliorated these effects. In conclusion, our results reveal a possible mechanism for AGE-induced pancreatic islet damage upon NLRP3 inflammasome activation.
Highlights
Advanced glycation end products (AGEs) are generated nonenzymatically, and the formation of AGEs is greatly accelerated by prolonged hyperglycemia in patients with diabetes mellitus (DM) [1, 2]
We explored whether the reactive oxygen species (ROS)/thioredoxininteracting protein (TXNIP) pathway contributes to AGE-induced NLRP3 inflammasome activation
We found that the administration of AGEs significantly increased the superoxide anion level through upregulation of NADPH oxidase 2 (NOX2) protein, which in turn contributed to an increase in expression levels of TXNIP and NLRP3 inflammasome components and an increase in protein interaction levels between TXNIP and NLRP3
Summary
Advanced glycation end products (AGEs) are generated nonenzymatically, and the formation of AGEs is greatly accelerated by prolonged hyperglycemia in patients with diabetes mellitus (DM) [1, 2]. Recent studies have pointed out that AGE accumulation directly causes insulinproducing β-cell dysfunction and apoptosis in vivo [6,7,8,9]. These effects are attributed, at least in part, to an increase in cellular reactive oxygen species (ROS) production. Inflammation is a critical mechanism leading to β-cell dysfunction and death, wherein the inflammatory cytokines play an important role [10, 11]. Clinical studies reported that inhibition of IL1β by either IL-1 receptor antagonist or IL-1β antibody in patients with type 2 DM leads to improvement in glycemia and β-cell function [12, 13]. It is known that IL-1β secretion is predominantly mediated by the cysteine protease caspase, which is mainly activated by inflammasomes, especially the nucleotide-binding domain leucine-rich repeat containing receptor, the pyrin domain-containing 3 (NLRP3) inflammasome [14]
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