Mounting evidence suggests that immunological mechanisms play a fundamental role in the pathogenesis of diabetic retinopathy (DR) and diabetic macular edema (DME). Upregulation of cytokines and other proinflammatory mediators leading to persistent low-grade inflammation is believed to actively contribute to the DR-associated damage to the retinal vasculature, inducing breakdown of the blood-retinal barrier, subsequent macular edema formation, and promotion of retinal neovascularization. This review summarizes the current knowledge of the biological processes providing an inflammatory basis for DR and DME. In addition, emerging therapeutic approaches targeting inflammation are discussed, including blockade of angiopoietin 2 and other molecular targets such as interleukin (IL)-6, IL-1β, plasma kallikrein, and integrins.

The role of inflammation in diabetic eye disease

Diabetic retinopathy (DR) is a diabetic complication which affects retinal function and results in severe loss of vision and relevant retinal diseases. Retinal vascular dysfunction caused by multifactors, such as advanced glycosylation end products and receptors, pro-inflammatory cytokines and chemokines, proliferator-activated receptor-γ disruption, growth factors, oxidative stress, and microRNA. These factors promote retinal endothelial dysfunction, which results in the development of DR. In this review, we summarize the contributors in the pathophysiology of DR for a better understanding of the molecular and cellular mechanism in the development of DR with a special emphasis on retinal endothelial dysfunction.

/pdf/endothelial-dysfunction-in-diabetic-retinopathy-4txyaslnb8.pdf

Endothelial Dysfunction in Diabetic Retinopathy.

Diabetic retinopathy (DR) is among the leading causes of new onset blindness in adults. Effective treatment may delay the onset and progression of this disease provided it is diagnosed early. At present retinopathy can only be diagnosed via formal examination of the eye by a trained specialist, which limits the population that can be effectively screened. An easily accessible, reliable screening biomarker of diabetic retinopathy would be of tremendous benefit in detecting the population in need of further assessment and treatment. This review highlights specific biomarkers that show promise as screening markers to detect early diabetic retinopathy or even to detect patients at increased risk of DR at the time of diagnosis of diabetes. The pathobiology of DR is complex and multifactorial giving rise to a wide array of potential biomarkers. This review provides an overview of these pathways and looks at older markers such as advanced glycation end products (AGEs), inflammatory markers, vascular endothelial growth factor (VEGF) as well as other newer proteins with a role in the pathogenesis of DR including neuroprotective factors such as brain derived neurotrophic factor (BDNF) and Pigment Epithelium Derived Factor (PEDF); SA100A12, pentraxin 3, brain natriuretic peptide, apelin 3, and chemerin as well as various metabolites such as lipoprotein A, folate, and homocysteine. We also consider the possible role of proteins identified through proteomics work whose levels are altered in the sera of patients with DR as screening markers though their role in pathophysiology remains to be characterized. The role of microRNA as a promising new screening marker is also discussed.

/pdf/molecular-markers-of-diabetic-retinopathy-potential-nxli0u7323.pdf

Molecular Markers of Diabetic Retinopathy: Potential Screening Tool of the Future?

Several studies have linked vascular endothelial growth factors (VEGFs) with metabolic syndrome or its components. However, there has been no systematic appraisal of the findings of these studies to date. The current systematic review and meta-analysis was conducted to explore this association. PubMed, EMBASE, the Cochrane library, and clinical trials registries were used to retrieve peer-reviewed clinical studies that had evaluated the association of VEGFs with metabolic syndrome or its components without applying language and date restrictions. The final search was performed on 29 September 2017. We included 32 studies in this systematic review and meta-analysis, of which 16 studies (19 study arms) were included in the meta-analysis and remaining studies were qualitatively assessed. Overall, VEGF-A, VEGF-B and VEGF-C were strongly associated with metabolic syndrome or its components. The components of metabolic syndrome varied in their association. Obesity was not correlated with increased VEGF-A expression (p = 0.12), whereas VEGF-B and VEGF-C expression was significantly higher in those with obesity. In contrast, hyperglycemia in type 1 diabetes was strongly associated with increased VEGF-A levels (p < 0.00001), as was type 2 diabetes (p = 0.0006). The studies included in the qualitative analysis similarly showed an increase in VEGF family expression in people with metabolic syndrome, and with its components. The increased concentrations of vascular endothelial growth factors are variably associated with metabolic syndrome or its components. Each VEGF protein has a unique set of associations with the disease state.

/pdf/association-between-the-expression-of-vascular-endothelial-ylzlpaw25o.pdf

Association between the expression of vascular endothelial growth factors and metabolic syndrome or its components: a systematic review and meta-analysis

Chemerin acts as a chemotactic factor for leukocyte populations expressing the G protein-coupled receptor CMKLR1 (ChemR23). It is also an adipocytokine involved in obesity and metabolic syndromes. Previous studies have demonstrated that chemerin promotes angiogenesis in vitro, although the precise mechanism has not been elucidated. In this study, we have investigated whether chemerin regulates angiogenic processes and validated the associated mechanisms. In this study, chemerin stimulated angiogenesis in mice, which was demonstrated using Matrigel plug implantation assay, mouse corneal models of angiogenesis, and ex vivo rat aortic ring assay. To explore the mechanisms by which chemerin induced angiogenesis, we examined the effects of chemerin in human umbilical vein endothelium cells (HUVECs). Chemerin stimulated the differentiation of HUVECs into capillary-like structures, promoted the proliferation of HUVECs, and functioned as a chemoattractant in migration assays. Chemerin induced the phosphorylation of Akt and p42/44 extracellular signal-regulated kinase (ERK) in HUVECs and chemerin promotes angiogenesis via Akt and ERK. SiRNA against the chemerin receptor CMKLR1 but not that against another chemerin receptor, CCRL2, completely inhibited the chemerin-induced migration and angiogenesis of HUVECs, which indicates that chemerin promotes the migration and angiogenic activities of HUVECs mainly through CMKLR1.

Chemerin promotes angiogenesis in vivo

Background: Interleukin-6 (IL-6) is produced by a variety of cells involved in inflammation and acts as local intensification signals in pathological processes associated with chronic eye inflammat...

Interleukin-6 and Diabetic Retinopathy: A Systematic Review and Meta-Analysis.

Purpose: To compare serum levels of chemerin in type 2 diabetes mellitus (T2DM) with or without retinopathy, and to investigate the relationship between serum chemerin levels and diabetes retinopathy.Materials and methods: A total of 60 T2DM patients and 20 healthy subjects (control group) were enrolled in this study. Of the T2DM patients, 15 had proliferative diabetic retinopathy (PDR group), 20 had non-proliferative retinopathy (NPDR group) and 25 had no retinopathy (T2DM group). Their serum samples were collected for testing the levels of chemerin, vascular endothelial growth factor (VEGF), C-reactive protein (CRP) and so on. The values were analyzed to compare the differences among the groups. Simple linear regression analysis and multiple stepwise linear regression analysis were used to determine the correlations between variables and chemerin. Trend chi-square was used to determine the correlations between chemerin and the severity of diabetic retinopathy (DR).Results: Chemerin levels in gro...

Increased Serum Chemerin Levels in Diabetic Retinopathy of Type 2 Diabetic Patients

Tumor necrosis factor-α and diabetic retinopathy: Review and meta-analysis.

Different effects of anti-VEGF drugs (Ranibizumab, Aflibercept, Conbercept) on autophagy and its effect on neovascularization in RF/6A cells

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Interleukin-6 and Diabetic Retinopathy: A Systematic Review and Meta-Analysis.

Increased Serum Chemerin Levels in Diabetic Retinopathy of Type 2 Diabetic Patients

Tumor necrosis factor-α and diabetic retinopathy: Review and meta-analysis.

Different effects of anti-VEGF drugs (Ranibizumab, Aflibercept, Conbercept) on autophagy and its effect on neovascularization in RF/6A cells