The eye is an immune privileged tissue that insulates the visual system from local and systemic immune provocation to preserve homeostatic functions of highly specialized retinal neural cells. If immune privilege is breached, immune stimuli will invade the eye and subsequently trigger acute inflammatory responses. Local resident microglia become active and release numerous immunological factors to protect the integrity of retinal neural cells. Although acute inflammatory responses are necessary to control and eradicate insults to the eye, chronic inflammation can cause retinal tissue damage and cell dysfunction, leading to ocular disease and vision loss. In this review, we summarized features of immune privilege in the retina and the key inflammatory responses, factors, and intracellular pathways activated when retinal immune privilege fails, as well as a highlight of the recent clinical and research advances in ocular immunity and ocular vascular diseases including retinopathy of prematurity, age-related macular degeneration, and diabetic retinopathy.
Background Pathological neovascularization in neovascular age-related macular degeneration (nAMD) is the leading cause of vision loss in the elderly. Increasing evidence shows that cells of myeloid lineage play important roles in controlling pathological endothelium formation. Suppressor of cytokine signaling 3 (SOCS3) pathway has been linked to neovascularization. Methods We utilised a laser-induced choroidal neovascularization (CNV) mouse model to investigate the neovascular aspect of human AMD. In several cell lineage reporter mice, bone marrow chimeric mice and Socs3 loss-of-function (knockout) and gain-of-function (overexpression) mice, immunohistochemistry, confocal, and choroidal explant co-culture with bone marrow-derived macrophage medium were used to study the mechanisms underlying pathological CNV formation via myeloid SOCS3. Findings SOCS3 was significantly induced in myeloid lineage cells, which were recruited into the CNV lesion area. Myeloid S ocs3 overexpression inhibited laser-induced CNV, reduced myeloid lineage-derived macrophage/microglia recruitment onsite, and attenuated pro-inflammatory factor expression. Moreover, SOCS3 in myeloid regulated vascular sprouting ex vivo in choroid explants and SOCS3 agonist reduced in vivo CNV. Interpretation These findings suggest that myeloid lineage cells contributed to pathological CNV formation regulated by SOCS3. Funding This project was funded by NIH/NEI (R01EY030140, R01EY029238), BrightFocus Foundation, American Health Assistance Foundation (AHAF), and Boston Children's Hospital Ophthalmology Foundation for YS and the National Institutes of Health/National Heart, Lung and Blood Institute (U01HL098166) for PZ.
Neovascularization is the leading cause of vision loss in retinopathy of prematurity (ROP). Inflammation and myeloid cells are involved in retinal angiogenesis. However, the underlying mechanisms of how myeloid cells control neovascularization in ROP remain unknown. We and others previously reported that suppressor of cytokine signaling 3 (SOCS3) is induced in retinopathy. To investigate whether myeloid cells regulate retinal angiogenesis via SOCS3 in ROP, we used myeloid lineage specific SOCS3 loss-of-function (conditional knockout, cKO) mice and gain-of-function (conditional overexpression, cOE) mice and generated ROP mouse model - mice with oxygen induced retinopathy (OIR) by exposing mice to 75% oxygen from postnatal day (P)7 to P12 for 5 days, and then returned to normal air until P17. Retinas were collected for analysis including quantification of retinal neovascularization, gene expression, immune cell profiling and single cell sequencing. Our results showed that mice with myeloid SOCS3 deficiency had a substantial increase in pathological retinal neovascularization, whereas overexpression of SOCS3 in myeloid cells prevented pathological retinal neovascularization in response to OIR. Our single-cell sequencing data showed that population of myeloid lineage cells including microglia, macrophages and neutrophils was changed in mice with OIR and controlled by SOCS3. Therefore, myeloid cells are involved in retinal neovascularization via SOCS3 in ROP. Manipulating SOCS3 expression in myeloid cells may provide a new way to cure neovascularization in retinas. Supported by grants from NIH (R01EY030140, R01EY029238) and from BrightFocus Foundation
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.