화학공학소재연구정보센터
Biochemical and Biophysical Research Communications, Vol.493, No.2, 1136-1142, 2017
TLR7 deficiency contributes to attenuated diabetic retinopathy via inhibition of inflammatory response
Diabetic retinopathy (DR) is a major microvascular complication of diabetes, resulting in neuronal dysfunction, retinal vascular leakage, and apoptosis within the retina. Innate immunity plays an important role in the pathogenesis of type 2 diabetes (T2D) and related complications. The toll-like receptors (TLRs), central to innate immunity, are essential participants in the progression and pathogenesis of the disease and its complications. In the study, streptozotocin (STZ) was combined with whole-body hypoxia for quicker induction of early-stage diabetic retinopathy (DR) in the wild type (WT) and TLR7-knockout (KO) C57BL/6 mice. The effects of TLR7 were also investigated in fructose-treated retinal pigment epithelial (RPE) cells. In the retinas of WT/DR mice, abnormal a-wave and b-wave activity, hyperfluorescence, and reduced retinal thickness were observed. DR development was associated with enhanced TLR7 expression, whose deletion dramatically reduced VEGF expression levels. And the secretion of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-113, IL 6, IL-18 and IL-12, was highly reduced by TLR7-deficiency in DR mice. Consistently, WT/DR mice exhibited higher phosphorylation of IKB kinase a (IKKa), inhibitor of NF-kappa B alpha (IKB alpha) and nuclear factor KB (NF-kappa B), which were found to be down-regulated in KO/DR mice. Similarly, DR-induced mitogen-activated protein kinases (MAPKs) activation was blocked by TLR7-knockout. In vitro, fructose incubation triggered inflammation was reversed by TLR7 knockdown, accompanied with inactivated NF-kappa B and MAPKs pathways. And reduced reactive oxygen species (ROS) generation was observed in TLR7knockdown cells with fructose treatment. Together, inhibiting TLR7 suppressed diabetic retinopathy by reducing inflammation and suggested a potential application in clinics. (c) 2017 Published by Elsevier Inc.