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MiR-17-5p Inhibits TXNIP/NLRP3 Inflammasome Pathway and Suppresses Pancreatic β-Cell Pyroptosis in Diabetic Mice.

ABSTRACT: Objective: Diabetes mellitus is a chronic progressive inflammatory metabolic disease with pancreatic β-cells dysfunction. The present study aimed to investigate whether miR-17-5p plays a protective effect on pancreatic β-cells function in diabetes mellitus (DM) mice and dissect the underlying mechanism. Methods: C57BL/6J mice were randomly divided into control, DM, DM + Lentivirus negative control (LV-NC), and DM + Lenti-OE™ miR-17-5p (LV-miR-17-5) groups. DM was established by feeding a high-fat diet and intraperitoneal injection with streptozotocin (STZ) in mice. Blood glucose and glucose tolerance in circulation were measured. Meanwhile, the activation of nod-like receptor protein 3 (NLRP3) inflammasome, pancreas pyroptosis, and the expression of miR-17-5p and thioredoxin-interacting protein (TXNIP) were detected in the pancreas of DM mice. Pancreatic β-cell line INS-1 subjected to different concentrations of glucose was used in in vitro experiments. Results: Compared with control mice, glucose tolerance deficit, elevated blood glucose level, and decreased pancreatic islet size, were presented in DM mice, which was associated with a downregulation of miR-17-5p. Importantly, exogenous miR-17-5p alleviated pancreas injury, and consequently improved glucose tolerance and decreased blood glucose in DM mice. In vitro experiments showed that high glucose decreased miR-17-5p expression and impaired insulin secretion in INS-1 cells. Mechanistically, miR-17-5p inhibited the expression of TXNIP and NLRP3 inflammasome activation, and thus decreased pancreatic β-cell pyroptosis. Conclusion: Our results demonstrated that miR-17-5p improves glucose tolerance, and pancreatic β-cell function and inhibits TXNIP/NLRP3 inflammasome pathway-related pyroptosis in DM mice.

SUBMITTER: Liu S

PROVIDER: S-EPMC8645844 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAtherosclerosis (AS) is chronic inflammatory arterial disorder. Artesunate could exhibit anti-inflammatory activity in AS, but its role in AS is still in its incipient stage. In this study, we explored the anti-inflammatory effect of artesunate in AS and its underlying mechanism.MethodsWe isolated CD14+ monocytes from peripheral blood (PB) of 115 coronary heart disease (CHD) patients and 33 non-CHD patients confirmed by coronary angiography. Phorbol myristate acetate (PMA) was used to induce the differentiation of THP-1 monocytes to macrophages. Cells were treated with artesunate at a final concentration of 2.5, 5 or 10 µmol/L. The activation of NLRP3 inflammasome was assessed by immunoblotting of apoptosis-associated speck-like protein containing caspase recruitment domain (ASC). The expression of pro-caspase-1/pro-interleukin (IL)-1β/pro-IL-18 and their mature forms was measured using immunoblotting. A rat model of AS was induced by vitamin D3 (VD3) and a 21-day high-fat diet.ResultsDownregulated miR-16-5p and upregulated thioredoxin-interacting protein (TXNIP) was determined in CD14+ monocytes from CHD patients and associated with disease severity. Artesunate abrogated the activation of NLRP3 inflammasome in the presence of inflammasome activators in cultured macrophages. Artesunate reduced TXNIP expression and impaired the interaction between TXNIP and NLRP3, thereby inhibiting release of inflammatory cytokines and ASC production in cultured macrophages. In addition, miR-16-5p negatively regulated the messenger RNA (mRNA) of TXNIP. Artesunate increased the expression of miR-16-5p in a dose-dependent manner, and inhibition of miR-16-5p enhanced the secretion of inflammatory cytokines. Our in vivo experiments also demonstrated that artesunate reduced lipid accumulation, atherosclerotic plaque formation, and antagonized inflammation in a dose-dependent manner by upregulating miR-16-5p.ConclusionsIn summary, the present study unveiled a mechanism underlying the anti-inflammatory role of artesunate in AS.

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MiR-17-5p Inhibits TXNIP/NLRP3 Inflammasome Pathway and Suppresses Pancreatic β-Cell Pyroptosis in Diabetic Mice.

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