Metformin Inhibits Advanced Glycation End Products-Induced Inflammatory Response in Murine Macrophages Partly through AMPK Activation and RAGE/NFκB Pathway Suppression.

Zhong’E Zhou,Liang Liu,Xian Jin,Chengxing Shen,Chengjun Chen,Yong Tang,Yi Lu

doi:10.1155/2016/4847812

Abstract

Advanced glycation end products (AGEs) are major inflammatory mediators in diabetes, affecting atherosclerosis progression via macrophages. Metformin slows diabetic atherosclerosis progression through mechanisms that remain to be fully elucidated. The present study of murine bone marrow derived macrophages showed that (1) AGEs enhanced proinflammatory cytokines (interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α)) mRNA expression, RAGE expression, and NFκB activation; (2) metformin pretreatment inhibited AGEs effects and AGEs-induced cluster designation 86 (CD86) (M1 marker) expression, while promoting CD206 (M2 marker) surface expression and anti-inflammatory cytokine (IL-10) mRNA expression; and (3) the AMPK inhibitor, Compound C, attenuated metformin effects. In conclusion, metformin inhibits AGEs-induced inflammatory response in murine macrophages partly through AMPK activation and RAGE/NFκB pathway suppression.

Highlights

Atherosclerosis, one of the main complications of diabetes, constitutes the leading cause of morbidity and mortality in today’s world
Our previous study elucidated that advanced glycation end products (AGEs) promoted Bone Marrow Derived Macrophages (BMDMs) to express proinflammatory cytokines through RAGE/NFκB signaling [7]
RAGE/ NFκB signaling is involved in AGEs-induced inflammatory response in macrophages

Summary

Introduction

Atherosclerosis, one of the main complications of diabetes, constitutes the leading cause of morbidity and mortality in today’s world. Previous studies have demonstrated that excessive inflammatory M1 monocytes/macrophages emerge in peripheral blood of both prediabetic and diabetic patients [4, 5]. Our previous study found that M1 monocytes/macrophages, the inflammatory subset, increased in circulation and atherosclerotic plaque in STZ-induced diabetic mice and were related to enhanced inflammation and accelerated atherosclerosis [6]. The increased inflammatory macrophages in diabetes contribute to persistent low grade inflammation and accelerated atherosclerosis. Various factors are responsible for macrophage inflammatory activation in diabetes. Previous studies showed AGEs driven inflammatory response in macrophages [7] and promoted atherosclerosis [8]. Because inflammatory macrophages dominate the progression of atherosclerosis, blockage or attenuation of AGEs-induced macrophage inflammatory response might alleviate diabetic atherosclerosis

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Discussion

Conclusion