MD2 activation by direct AGE interaction drives inflammatory diabetic cardiomyopathy

Yi Wang,Gaojun Wu,Xuemei Chen,Wu Luo,Hazel Lum,Jibo Han,Meihong Wang,Qilu Fang,Guang Liang,Weijian Huang,Yiyi Jin,Yali Zhang,Zia A. Khan,Jianchang Qian

doi:10.1038/s41467-020-15978-3

Abstract

Hyperglycemia activates toll-like receptor 4 (TLR4) to induce inflammation in diabetic cardiomyopathy (DCM). However, the mechanisms of TLR4 activation remain unclear. Here we examine the role of myeloid differentiation 2 (MD2), a co-receptor of TLR4, in high glucose (HG)- and diabetes-induced inflammatory cardiomyopathy. We show increased MD2 in heart tissues of diabetic mice and serum of human diabetic subjects. MD2 deficiency in mice inhibits TLR4 pathway activation, which correlates with reduced myocardial remodeling and improved cardiac function. Mechanistically, we show that HG induces extracellular advanced glycation end products (AGEs), which bind directly to MD2, leading to formation of AGEs-MD2-TLR4 complex and initiation of pro-inflammatory pathways. We further detect elevated AGE-MD2 complexes in heart tissues and serum of diabetic mice and human subjects with DCM. In summary, we uncover a new mechanism of HG-induced inflammatory responses and myocardial injury, in which AGE products directly bind MD2 to drive inflammatory DCM.

Highlights

Hyperglycemia activates toll-like receptor 4 (TLR4) to induce inflammation in diabetic cardiomyopathy (DCM)
Our findings indicate that high glucose (HG) triggers rapid generation of advanced glycation end products (AGEs), which directly bind myeloid differentiation 2 (MD2) and lead to the activation of MD2-TLR4 signaling complex and inflammatory cardiac tissue injury
The findings suggest that upregulated MD2 may primarily be derived from cardiomyocytes and infiltrated macrophages

Summary

Introduction

Hyperglycemia activates toll-like receptor 4 (TLR4) to induce inflammation in diabetic cardiomyopathy (DCM). We examine the role of myeloid differentiation 2 (MD2), a co-receptor of TLR4, in high glucose (HG)- and diabetes-induced inflammatory cardiomyopathy. We show that HG induces extracellular advanced glycation end products (AGEs), which bind directly to MD2, leading to formation of AGEsMD2-TLR4 complex and initiation of pro-inflammatory pathways. We uncover a new mechanism of HG-induced inflammatory responses and myocardial injury, in which AGE products directly bind MD2 to drive inflammatory DCM. Our findings indicate that HG triggers rapid generation of advanced glycation end products (AGEs), which directly bind MD2 and lead to the activation of MD2-TLR4 signaling complex and inflammatory cardiac tissue injury. We present a mechanism by which hyperglycemia triggers inflammatory injury in DCM, which underscores the importance of MD2 as a new potential key therapeutic target for DCM

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