Abstract
Diabetic retinopathy (DR) causes visual impairment in working age adults and hyperglycemia-mediated inflammation is central in DR. Toll-like receptors (TLRs) play a key role in innate immune responses and inflammation. However, scanty data is available on their role in DR. Hence, in this study, we examined TLR2 and TLR4 mRNA and protein expression and activity in hyperglycemic human retinal endothelial cells (HMVRECs). HMVRECs were treated with hyperglycemia (HG) or euglycemia and mRNA and protein levels of TLR-2, TLR-4, MyD88, IRF3, and TRIF as well as NF-κB p65 activation were measured. IL-8, IL-1β, TNF-α and MCP-1, ICAM-1, and VCAM-1 as well as monocyte adhesion to HMVRECs were also assayed. HG (25 mM) significantly induced TLR2 and TLR4 mRNA and protein in HMVRECs. It also increased both MyD88 and non-MyD88 pathways, nuclear factor-κB (NF-κB), biomediators, and monocyte adhesion. This inflammation was attenuated by TLR-4 or TLR-2 inhibition, and dual inhibition by a TLR inhibitory peptide as well as TLR2 and 4 siRNA. Additionally, antioxidant treatment reduced TLR-2 and TLR4 expression and downstream inflammatory markers. Collectively, our novel data suggest that hyperglycemia induces TLR-2 and TLR-4 activation and downstream signaling mediating increased inflammation possibly via reactive oxygen species (ROS) and could contribute to DR.
Highlights
RDiabetes is a growing global epidemic affecting nearly 36 explain how hyperglycemia can induce Diabetic retinopathy (DR) include the polyol pathway, activation of protein kinase-C (PKC), increased oxidative stress, advanced glycation end product (AGE)million people in USA alone and nearly 350 million world- formation, and increased inflammation [2, 7,8,9]
In the current study we report that, in human microvascular retinal endothelial cells (HMVRECs), there is an increase in adhesion molecules such as intracellular adhesion molecule- (ICAM-)1 and VCAM
Our study clearly points towards a role for Toll-like receptors (TLRs)-4and TLR-2-induced inflammation in the genesis of DR
Summary
Million people in USA alone and nearly 350 million world- formation, and increased inflammation [2, 7,8,9]. Diabetic retinopathy (DR) is the leading cause of increased oxidative stress and AGE receptor engagement vision impairment and blindness among working adults can result in increased inflammation. Inflammation results in an increase in NF-κB els of C-reactive protein (CRP), inflammatory cytokines, activity, cytokines, chemokines, adhesion molecules, leukochemokines, adhesion molecules, monocyte activity, and adi- cyte adhesion, and leukostasis [2, 9, 10]. Hyperglycemia in diabetes mechanism behind hyperglycemia-mediated inflammation contributes to microvascular complications and reduction of leading to microvascular complications is unclear
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