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.
Highlights
Ischemic retinopathies are leading causes of blindness globally, from conditions including diabetic retinopathy, retinal vein occlusions, and retinopathy of prematurity
We first investigated the presence of microglia/macrophages in post-mortem human specimens in non-diabetic retina and nonproliferative diabetic retinopathy using immunohistochemical analysis with IBA1, which has been found to be a more specific marker in detecting both quiescent and activated Mononuclear phagocytes (MPs) in CNS [26], and which has been a useful marker of microglia in the retinal studies, including retinal disease models [13, 27, 28]
We further investigated the presence of microglia/macrophages in non-diabetic, nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) cases with immunofluorescent staining
Summary
Ischemic retinopathies are leading causes of blindness globally, from conditions including diabetic retinopathy, retinal vein occlusions, and retinopathy of prematurity. Capillary dropout and lack of revascularization characterize these diseases, with consequent upregulation of pro-angiogenic growth factors by ischemic retina that stimulates pathologic pre-retinal angiogenesis. A proinflammatory state including upregulation of cytokines like TNF- is thought to impair reparative angiogenesis in ischemic retina [1, 2]. There is a great need for further understanding of the mechanisms regulating the retinal milieu and vasculature in ischemia. Investigation has intensified with regard to non-vascular cellular elements of the neurovascular unit that regulate the retinal vasculature [3]. Mononuclear phagocytes (MPs), such as microglia/macrophages, are increasingly linked to ischemic retinopathies [8]. A pivotal study implicated myeloid cells in regulation of ischemia-induced retinal angiogenesis. Neuropilin-1-positive mononuclear phagocytes exacerbated pathologic neovascularization in a mouse model of ischemic retinopathy [9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
