Myeloid cell modulation by a GLP-1 receptor agonist regulates retinal angiogenesis in ischemic retinopathy
Lingli Zhou, … , Seulki Lee, Elia J. Duh
Lingli Zhou, … , Seulki Lee, Elia J. Duh
Published October 21, 2021
Citation Information: JCI Insight. 2021;6(23):e93382. https://doi.org/10.1172/jci.insight.93382.
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Research Article Ophthalmology

Myeloid cell modulation by a GLP-1 receptor agonist regulates retinal angiogenesis in ischemic retinopathy

Abstract

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.

Authors

Lingli Zhou, Zhenhua Xu, Yumin Oh, Rico Gamuyao, Grace Lee, Yangyiran Xie, Hongkwan Cho, Seulki Lee, Elia J. Duh

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Figure 1

Microglial/macrophage activation in human diabetic retina, PDR membrane, and mice OIR retina.

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Microglial/macrophage activation in human diabetic retina, PDR membrane,...
(A) MPs were immunostained with IBA1 antibody (blue) in nondiabetic and NPDR human eyes. In nondiabetic retina, ramified microglia (blue arrowhead) are presented in inner retinal layers. Hypertrophic MPs (green arrowhead) were observed in NPDR retina. n = 3. Scale bar: 100 μm. (B) Representative images of immunofluorescence (IF) staining of microglia/macrophages (red) in nondiabetic (left), NPDR (middle), and PDR (right) human eyes. In the nondiabetic control cases, IBA1 staining was weak. There were significantly more amoeboid microglia (yellow arrowheads) in both NPDR and PDR retinas. Blue: DAPI staining. (n = 6, nondiabetic eyes; n = 5 NPDR eyes; n = 6 PDR eyes). Scale bar: 100 μm. (C) Representative images of IHC staining of IBA1+ microglia/macrophages (blue) in membranes from patients with active PDR. Images were taken using a ×63 objective. Nuclear fast red was used for counterstaining. n = 3. Scale bar: 100 μm. (D) Representative IF staining of MPs (red) and TNF-α (green) in PDR membranes. Blue: DAPI staining. Scale bar: 100 μm. (E) Schematic diagram of OIR. Neonatal mice were exposed to 75% oxygen from P7 to P12 to induce vaso-obliteration and returned to room air from P12 to P17 to induce physiological revascularization and pathological NV, which reached maximum at P17. (F) Representative IF images of vasculature (IB4, red) and IBA1+ MPs (green) in retinal flat mounts from P17 OIR and room air (n = 3 mice). Scale bar: 100 μm.