Inhibition of vascular endothelial growth factor alleviates neovascular retinopathy with regulated neurotrophic/proinflammatory cytokines through the modulation of DBI-TSPO signaling

被引：8

作者：

Gao, Shuang ^{[1
]}

Li, Na ^{[1
]}

Wang, Yanuo ^{[1
]}

Lin, Zhongjing ^{[2
]}

Zhu, Yanji ^{[1
]}

Xu, Jianmin ^{[1
]}

Zhang, Qiong ^{[1
]}

Zhu, Caihong ^{[1
]}

Zhou, Yingming ^{[1
]}

Zhou, Jia ^{[3
]}

Shen, Xi ^{[1
]}

机构：

[1] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Dept Ophthalmol, 197 Ruijin Er Rd, Shanghai 200025, Peoples R China

[2] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Ophthalmol, Shanghai, Peoples R China

[3] Shanghai Jiao Tong Univ, Sch Med, LuWan Branch, Dept Ophthalmol,Ruijin Hosp, Shanghai 200025, Peoples R China

来源：

FASEB JOURNAL | 2022年 / 36卷 / 07期

关键词：

diazepam binding inhibitor; microglial cell; Muller cell; translocator protein (18 kDa); vascular endothelial growth factor; PROLIFERATIVE DIABETIC-RETINOPATHY; OXYGEN-INDUCED RETINOPATHY; PROTEIN; 18; KDA; MULLER CELLS; RETINAL NEURONS; MOUSE MODEL; MICROGLIA; VEGF; EXPRESSION; GLIA;

D O I：

10.1096/fj.202101294RRR

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Diazepam binding inhibitor (DBI)-translocator protein (18kDa) (TSPO) signaling in the retina was reported to possess coordinated macroglia-microglia interactions. We investigated DBI-TSPO signaling and its correlation with vascular endothelial growth factor (VEGF), neurotrophic or inflammatory cytokines in neovascular retinopathy, and under hypoxic conditions. The vitreous expression of DBI, VEGF, nerve growth factor (NGF), and interleukin-1beta (IL-1 beta) were examined in proliferative diabetic retinopathy (PDR) patients with or without anti-VEGF therapy and nondiabetic controls. Retinal DBI-TSPO signaling and the effect of the anti-VEGF agent were evaluated in a mouse model of oxygen-induced retinopathy (OIR). Interactions between Muller cell-derived VEGF and DBI, as well as cocultured microglial cells under hypoxic conditions, were studied, using Western blot, real-time RT-PCR, enzyme-linked immunosorbent assay (ELISA), flow cytometry, and immunofluorescent labeling. Results showed that vitreous levels of DBI, VEGF, NGF, and IL-1 beta were significantly higher in PDR patients compared with controls, which further changed after anti-VEGF therapy. A statistical association was found between vitreous DBI and VEGF, NGF, IL-1 beta, and age. The application of the anti-VEGF agent in the OIR model induced retinal expression of DBI and NGF, and attenuated inflammation and microglial cell activation. Inhibition of Muller cell-derived VEGF could increase its DBI expression under hypoxic conditions, while the DBI-TSPO signaling pathway is essential for anti-VEGF agents exerting anti-inflammatory and neuroprotective effects, as well as limiting inflammatory magnitude, promoting its neurotrophin production and anti-inflammatory (M2) polarization in microglial cells. These findings suggest the beneficial effect of anti-VEGF therapy on inflammation and neurotrophy of retinal glial cells through modulation of the DBI-TSPO signaling pathway.

引用

页数：19

共 53 条

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