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

Sijun Liu,Jianfeng Gong,Cheng Zeng,Hongmei Tan,Fengqi Duan,Ge Tang,Yanming Chen

doi:10.3389/fcvm.2021.768029

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.

Highlights

Diabetes mellitus is a serious public health concern globally, with a growing incidence caused by genetic or unhealthy lifestyle habits [1]
Our results demonstrated that miR-17-5p improves glucose tolerance, and pancreatic β-cell function and inhibits thioredoxininteracting protein (TXNIP)/nod-like receptor protein 3 (NLRP3) inflammasome pathway-related pyroptosis in Diabetes mellitus (DM) mice
When INS-1 cells were incubated in high glucose (25 and 50 mmol/L), the expression of miR-17-5p was significantly down-regulated, demonstrating that high glucose resulted in decreased expression of miR-17-5p in a dose-dependent model (Figure 1A)

Summary

Introduction

Diabetes mellitus is a serious public health concern globally, with a growing incidence caused by genetic or unhealthy lifestyle habits [1]. Diabetes mellitus (DM) is characterized by long-term hyperglycemia resulting from the defect of insulin production and insulin resistance of insulin-responsive tissue and results in a series of chronic complications [2]. Nod-like receptor protein 3 (NLRP3) inflammasome has a critically important role in the regulation of inflammation in the development of DM [4]. It was reported that thioredoxininteracting protein (TXNIP), a multifunctional and inducible protein, regulates redox homeostasis in the cells [9, 10]. Increased expression of TXNIP functions as a major role in β cell failure and dysfunction during diabetes development [11]. TXNIP exacerbates NLRP3 inflammasome activation and provokes oxidative stress [12]. Inhibiting TXNIP/NLRP3 inflammasome pathway becomes a new therapeutic strategy in DM induced by an excessive inflammatory response

Methods

Results

Conclusion