High‐mobility group box‐1 and biomarkers of inflammation in the vitreous from patients with proliferative diabetic retinopathy

Abstract

PurposeTo measure levels of high-mobility group box −1 (HMGB1) and soluble receptor for advanced glycation end products (sRAGE) in the vitreous fluid from patients with proliferative diabetic retinopathy (PDR) and to correlate their levels with clinical disease activity and the levels of the inflammatory biomarkers monocyte chemoattractant protein-1 (MCP-1), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin-1β (IL-1β), and granulocyte macrophage colony-stimulating factor (GM-CSF). In addition, we examined the expression of HMGB1 in the retinas of diabetic mice.MethodsVitreous samples from 29 PDR and 17 nondiabetic patients were studied by enzyme-linked immunosorbent assay. Retinas of mice were examined by immunofluorescence analysis and western blotting.ResultsHMGB1 was detected in all vitreous samples and sRAGE was detected in 5 PDR samples. IL-1β was detected in 3PDR samples and GM-CSF was not detected. Mean HMGB1 levels in PDR with active neovascularization were twofold and threefold higher than that in inactive PDR and nondiabetic patients, respectively. Mean HMGB1 levels in PDR patients with hemorrhage were significantly higher than those in PDR patients without hemorrhage and nondiabetic patients (p=0.0111). There were significant correlations between levels of HMGB1 and levels of MCP-1 (r=0.333, p=0.025) and sICAM-1 (r=0.548, p<0.001). HMGB1 expression was also upregulated in the retinas of diabetic mice.ConclusionsSubclinical chronic inflammation might contribute to the progression of PDR.

The proinflammatory cytokine high‐mobility group box‐1 mediates retinal neuropathy induced by diabetes

“…expression in the vitreous fluid and preretinal membranes from patients with PDR and its expression correlated with the activity of the disease and the levels of inflammatory biomarkers [20][21][22]. In addition, we demonstrated that HMGB1 expression was upregulated in the retinas of diabetic mice and rats [21,23].…”

“…In addition, we demonstrated increased levels of HMGB1 in the vitreous samples from patients with PDR and that there were significant positive correlations between the vitreous levels of HMGB1 and the levels of the inflammatory biomarkers [20][21][22]. Furthermore, we demonstrated that diabetes induced significant upregulation of the expression of HMGB1 and RAGE in the retinas of rats and mice and that intravitreal administration of HMGB1 to normal rats induced activation of inflammatory signaling pathways in the retina and increased retinal vascular permeability [21,23].…”

Proliferative Diabetic Retinopathy: An Overview of Vitreous Immune and Biomarkers

“…This leakage can cause diabetic macular edema (DME) [5]. Several studies have shown marked increases of VEGF in vitreous and vitreous compared to plasma concentration in DME and PDR patients [19,[36][37][38][39][40][41][42][43][44][45][46]. Treatments that target VEGF have been proven highly effective in treating DR. VEGF antibodies, which were originally used for cancer treatments, such as bevacizumab and its correlate ranibizumab have been used effectively.…”

Role of matrix metalloproteinase-2 and -9 in the development of diabetic retinopathy

“…It is believed that the sustained high level of blood glucose in diabetes induces acellular capillaries and pericyte ghosts in retinal microvasculature by unknown mechanisms. Development of DR is a multifarious process where proteases, growth factors, cytokines, and chemokines such as monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1, stromal cell-derived factor-1α (SDF-1α), cyclooxygenase-2 (COX-2) and prostaglandin E2 production, vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), and connective tissue growth factor are released from retinal cells under hyperglycemia and interact with each other as well as activate several signaling pathways to promote neovascularization and fibrosis in the retina [7][8][9][10][11]. Considerable experimental evidence, generated in both tissue culture and animal models, indicate that in diabetes, retinal cells undergoes accelerated apoptosis and induces acellular capillaries and pericyte ghosts in retinal vasculature by unknown mechanism [12][13][14].…”