Abstract
BackgroundHyperglycemia-induced inflammation causes the dysfunction of blood vessels, and Toll-like receptor 4 (TLR4) plays a key role in inflammation-induced angiogenesis. However, the impact of TLR4 on the pathogenesis of diabetic retinopathy (DR) is poorly understood. In this study, we examined the expression of TLR4 in retinal vascular endothelial cells of patients with DR and diabetic mice, and explored the role of TLR4 in mediating inflammatory responses by human microvascular endothelial cells (HMEC-1) under high-glucose condition.MethodsThe expression of TLR4 in retinal vascular endothelial cells of patients with proliferative diabetic retinopathy and diabetic mice induced by streptozotocin was examined using immunofluorescence. HMEC-1 cells were cultured and the expression of TLR4, MyD88 and Interleukin-1β (IL-1β) was examined under high-glucose condition. Endothelial cells with TLR4 silencing and antagonist of TLR4 as well as endothelial cells from TLR4 deficient mice were used to study the effect of activated TLR4 on inflammation induced by high-glucose treatment.ResultsWe observed that TLR4 was detected in CD31-labled human retinal vascular endothelia and its expression was markedly increased in fibrovascular membranes from DR patients and in retinal vascular endothelial cells of diabetic mice. The expression of TLR4, MyD88 and IL-1β was enhanced by high glucose in cultured HMEC-1 and the expression of TLR4 and IL-1β was inhibited by TLR4 siRNA knock-down and TLR4 antagonist. The expression of IL-1β by endothelial cells from TLR4 deficient mice under high glucose condition was decreased.ConclusionsOur results revealed that hyperglycemia induced overexpression and activation of TLR4 in endothelial cells. This effect may lead to inflammatory responses contribute to the pathogenesis of diabetic retinopathy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13098-015-0086-4) contains supplementary material, which is available to authorized users.
Highlights
Hyperglycemia-induced inflammation causes the dysfunction of blood vessels, and Toll-like receptor 4 (TLR4) plays a key role in inflammation-induced angiogenesis
We examined the role of TLR4dependent pathway in high glucose-induced inflammatory responses in retinal vascular endothelial cells
The expression of TLR4 in premembrane of diabetic retinopathy patients Our previous study showed that TLR4 played a critical role in inflammation-induced angiogenesis in a mouse model
Summary
Hyperglycemia-induced inflammation causes the dysfunction of blood vessels, and Toll-like receptor 4 (TLR4) plays a key role in inflammation-induced angiogenesis. We examined the expression of TLR4 in retinal vascular endothelial cells of patients with DR and diabetic mice, and explored the role of TLR4 in mediating inflammatory responses by human microvascular endothelial cells (HMEC-1) under high-glucose condition. Diabetic retinopathy (DR) is a common microvascular complication of diabetes It remains the major cause of blindness in developed countries. Inflammation confers an increased risk for microvascular and macrovascular complications of diabetes. Endothelial cells are key participants in retinal ischemic vasculopathies and their dysfunction is the initial event of microvascular disorder in DR [3]. Chronic inflammatory responses in retinal endothelia cause the production of inflammatory mediators, leading to increased vascular permeability, apoptosis of endothelial cells and neovascularization [3]. Hyperglycemia, one of the major risk factors for DR, could trigger inflammation and leads to vascular complications. Upon exposure to high glucose, endothelial cells show a series of inflammatory responses, such as reduced NO production [4], but enhanced NF-κB activation [5], inflammatory gene expression [6]
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