MD2 activation by direct AGE interaction drives inflammatory diabetic cardiomyopathy

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.

Pattern recognition receptor‐mediated inflammation in diabetic vascular complications

“…In diabetes, high glucose (HG)-induced AGEs may activate TLRs and trigger inflammation. 8,14 The correlation between TLR activation and DVCs has been addressed in many studies. 70,[75][76][77] In addition, data from preclinical studies indicate that disrupting TLR activation provides beneficial effects in diabetic nephropathy 78 and cardiomyopathy.…”

“…[5][6][7] These complications are frequently associated with increased production of inflammatory cytokines such as tumor necrosis factor (TNF), interleukin 1β (IL-1β), and IL-6. [8][9][10] Emerging evidence shows that chronic sterile inflammation through innate immune responses contributes to diabetes and DVCs. 3,11,12 Our innate immune system utilizes distinct classes of germline-encoded pattern recognition receptors (PRRs), which sense a diverse set of sterile stimuli termed danger-associated molecular patterns (DAMPs), to initiate downstream inflammatory cascades.…”

“…11,13 In diabetes, persistently elevated levels of glucose accelerate the production of AGEs which may act as DAMPs to activate PRRs and incite chronic inflammation. 8,14…”

“…Although the underlying mechanisms of hyperglycemia‐induced damage are not thoroughly understood, the etiology of DVCs is believed to be closely related to oxidative stress, excessive production of advanced glycation end‐products (AGEs), and chronic inflammatory responses 5–7 . These complications are frequently associated with increased production of inflammatory cytokines such as tumor necrosis factor (TNF), interleukin 1β (IL‐1β), and IL‐6 8–10 . Emerging evidence shows that chronic sterile inflammation through innate immune responses contributes to diabetes and DVCs 3,11,12 .…”

“…Our innate immune system utilizes distinct classes of germline‐encoded pattern recognition receptors (PRRs), which sense a diverse set of sterile stimuli termed danger‐associated molecular patterns (DAMPs), to initiate downstream inflammatory cascades 11,13 . In diabetes, persistently elevated levels of glucose accelerate the production of AGEs which may act as DAMPs to activate PRRs and incite chronic inflammation 8,14 …”