VEGF-Independent Activation of Muller Cells by the Vitreous from Proliferative Diabetic Retinopathy Patients

Proliferative diabetic retinopathy (PDR), a major complication of diabetes mellitus, results from an inflammation-sustained interplay among endothelial cells, neurons, and glia. Even though anti-vascular endothelial growth factor (VEGF) interventions represent the therapeutic option for PDR, they are only partially efficacious. In PDR, Muller cells undergo reactive gliosis, produce inflammatory cytokines/chemokines, and contribute to scar formation and retinal neovascularization. However, the impact of anti-VEGF interventions on Muller cell activation has not been fully elucidated. Here, we show that treatment of MIO-M1 Muller cells with vitreous obtained from PDR patients stimulates cell proliferation and motility, and activates various intracellular signaling pathways. This leads to cytokine/chemokine upregulation, a response that was not mimicked by treatment with recombinant VEGF nor inhibited by the anti-VEGF drug ranibizumab. In contrast, fibroblast growth factor-2 (FGF2) induced a significant overexpression of various cytokines/chemokines in MIO-M1 cells. In addition, the FGF receptor tyrosine kinase inhibitor BGJ398, the pan-FGF trap NSC12, the heparin-binding protein antagonist N-tert-butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe Boc2, and the anti-inflammatory hydrocortisone all inhibited Muller cell activation mediated by PDR vitreous. These findings point to a role for various modulators beside VEGF in Muller cell activation and pave the way to the search for novel therapeutic strategies in PDR.

Automated summary

Proliferative diabetic retinopathy (PDR) is a major complication of diabetes mellitus, resulting from inflammation among endothelial cells, neurons, and glia. While anti-vascular endothelial growth factor (VEGF) interventions are the current therapeutic option for PDR, their impact on Muller cell activation remains unclear. Additional modulators besides VEGF have been found to play a role in Muller cell activation, suggesting potential for novel therapeutic strategies in PDR.