Wilmer Eye Institute and.
The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
JCI Insight. 2021 Dec 8;6(23):e93382. doi: 10.1172/jci.insight.93382.
Ischemic retinopathies including diabetic retinopathy are major causes of blindness. Although neurons and Müller glia are recognized as important regulators of reparative and pathologic angiogenesis, the role of mononuclear phagocytes (MPs) - particularly microglia, the resident retinal immune cells - is unclear. Here, we found MP activation in human diabetic retinopathy, especially in neovessels from human neovascular membranes in proliferative retinopathy, including TNF-α expression. There was similar activation in the mouse oxygen-induced retinopathy (OIR) model of ischemia-induced neovascularization. Glucagon-like peptide-1 receptor (GLP-1R) agonists are in clinical use for glycemic control in diabetes and are also known to modulate microglia. Herein, we investigated the effect of a long-acting GLP-1R agonist, NLY01. Following intravitreal administration, NLY01 selectively localized to MPs in retina with OIR. NLY01 modulated MPs but not retinal endothelial cell viability, apoptosis, and tube formation in vitro. In OIR, NLY01 treatment inhibited MP infiltration and activation, including MP expression of cytokines in vivo. NLY01 significantly suppressed global induction of retinal inflammatory cytokines, promoted reparative angiogenesis, and suppressed pathologic retinal neovascularization. Collectively, these findings indicate the important role of mononuclear phagocytes in regulation of retinal vascularization in ischemia and suggest modulation of MPs as a potentially new treatment strategy for ischemic retinopathies.
缺血性视网膜病变，包括糖尿病性视网膜病变，是失明的主要原因。虽然神经元和 Muller 胶质细胞被认为是修复性和病理性血管生成的重要调节因子，但单核吞噬细胞（MPs）的作用——特别是小胶质细胞，作为常驻视网膜免疫细胞——尚不清楚。在这里，我们发现了人糖尿病性视网膜病变中 MP 的激活，特别是在增生性视网膜病变中的人新生血管膜中的新血管中，包括 TNF-α的表达。在缺血性新生血管形成的小鼠氧诱导性视网膜病变（OIR）模型中也观察到类似的激活。胰高血糖素样肽-1 受体（GLP-1R）激动剂目前用于糖尿病的血糖控制，并且已知也可调节小胶质细胞。在此，我们研究了长效 GLP-1R 激动剂 NLY01 的作用。在玻璃体内给药后，NLY01 选择性地定位于具有 OIR 的视网膜中的 MPs。NLY01 可调节 MPs，但不影响体外视网膜内皮细胞的活力、凋亡和管形成。在 OIR 中，NLY01 治疗抑制了 MP 的浸润和激活，包括体内 MP 表达细胞因子。NLY01 显著抑制了视网膜炎症细胞因子的全身诱导，促进了修复性血管生成，并抑制了病理性视网膜新生血管形成。总之，这些发现表明单核吞噬细胞在调节缺血性视网膜血管生成中起着重要作用，并提示调节 MPs 可能是治疗缺血性视网膜病变的一种新的潜在治疗策略。
