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Myeloid cell modulation by a GLP-1 receptor agonist regulates retinal angiogenesis in ischemic retinopathy
Lingli Zhou1, Zhenhua Xu1, Yumin Oh1,2
1Wilmer Eye Institute and.
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.
Insights
Mononuclear phagocytes (MPs) drive vision loss in ischemic retinopathies. A GLP-1R agonist, NLY01, targets MPs, reducing inflammation and suppressing abnormal blood vessel growth in retinopathy models.
Area of Science:
- Ophthalmology
- Immunology
- Vascular Biology
Background:
- Ischemic retinopathies, like diabetic retinopathy, are leading causes of blindness.
- Mononuclear phagocytes (MPs), including microglia, play an unclear role in retinal neovascularization.
- MPs are activated in human diabetic retinopathy and in models of retinal ischemia.
Purpose of the Study:
- To investigate the role of MPs in ischemic retinopathy.
- To evaluate the therapeutic potential of a glucagon-like peptide-1 receptor (GLP-1R) agonist, NLY01, in modulating MP function.
- To determine if NLY01 can prevent or treat pathological retinal neovascularization.
Main Methods:
- Analysis of human diabetic retinopathy samples for MP activation.
- Utilized the oxygen-induced retinopathy (OIR) mouse model.
- Administered NLY01 intravitreally and assessed its effects on MPs and retinal neovascularization in vitro and in vivo.
Main Results:
- NLY01 selectively localized to MPs in OIR retinas.
- NLY01 inhibited MP infiltration and activation, including cytokine production.
- NLY01 suppressed retinal inflammatory cytokines, promoted reparative angiogenesis, and reduced pathological neovascularization.
Conclusions:
- Mononuclear phagocytes are key regulators of retinal vascularization during ischemia.
- Modulating MPs with agents like NLY01 represents a promising new therapeutic strategy for ischemic retinopathies.
- NLY01 effectively targets MPs to combat pathological neovascularization in the eye.
