Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, 25123 Brescia, Italy.
Eye Clinic, Department of Neurological and Vision Sciences, University of Brescia, 25123 Brescia, Italy.
Int J Mol Sci. 2021 Feb 22;22(4):2179. doi: 10.3390/ijms22042179.
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, Müller cells undergo reactive gliosis, produce inflammatory cytokines/chemokines, and contribute to scar formation and retinal neovascularization. However, the impact of anti-VEGF interventions on Müller cell activation has not been fully elucidated. Here, we show that treatment of MIO-M1 Müller 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 Müller cell activation mediated by PDR vitreous. These findings point to a role for various modulators beside VEGF in Müller cell activation and pave the way to the search for novel therapeutic strategies in PDR.
增生性糖尿病视网膜病变（PDR）是糖尿病的主要并发症，源于内皮细胞、神经元和神经胶质之间持续的炎症相互作用。尽管抗血管内皮生长因子（VEGF）干预是治疗 PDR 的选择，但它们仅部分有效。在 PDR 中，Müller 细胞发生反应性胶质增生，产生炎症细胞因子/趋化因子，并有助于瘢痕形成和视网膜新生血管形成。然而，抗 VEGF 干预对 Müller 细胞激活的影响尚未完全阐明。在这里，我们表明，用来自 PDR 患者的玻璃体处理 MIO-M1 Müller 细胞会刺激细胞增殖和运动，并激活各种细胞内信号通路。这导致细胞因子/趋化因子的上调，而用重组 VEGF 处理或用抗 VEGF 药物 ranibizumab 抑制均不能模拟这种反应。相比之下，成纤维细胞生长因子 2（FGF2）在 MIO-M1 细胞中引起各种细胞因子/趋化因子的显著过表达。此外，FGFR 酪氨酸激酶抑制剂 BGJ398、泛 FGF 陷阱 NSC12、肝素结合蛋白拮抗剂 N-tert-butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe Boc2 和抗炎性的氢化可的松均抑制了由 PDR 玻璃体介导的 Müller 细胞激活。这些发现表明，在 Müller 细胞激活中，除了 VEGF 之外，还有各种调节剂起作用，并为 PDR 中寻找新的治疗策略铺平了道路。
