Myeloid lineage contributes to pathological choroidal neovascularization formation via SOCS3

Abstract

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.

Suppressor of Cytokine Signaling 3 Derived Peptide as a Therapeutic for Inflammatory, and Oxidative Stress Induced Damage to the Retina

“…In the same vein, Multiple Sclerosis (MS) patients on simvastatin therapy showed elevation in SOCS3 levels that resulted in decreased STAT3 phosphorylation and decreased IL-6 and IL-17 levels (54,55). SOCS3 has been shown to prevent choroidal neovascularization in several studies (56)(57)(58)(59) and has been shown to be a regulator of infection and inflammation (60,61). Recently, the use of KIR peptide from SOCS3, attached to TAT protein domain for the purpose of cell penetration was reported in two publications from the same group for the suppression of IL-6 signaling in a model of traumatic brain injury (62,63).…”

Evaluation of sex differences in laser-induced choroidal neovascularization severity, phenotype and disease progression

“…Although the present findings are highly significant to standardization of the laser-induced CNV model, they should still be interpreted cautiously, and potential sex differences in specific disease processes or putative therapeutics should still be assessed. For example, microglia contribute significantly to the progression and severity of laser-induced CNV [45][46][47][48], and prior studies have suggested that microglial biology significantly differs between sexes [49,50]. Other processes of the inflammatory response to CNV, for example peripheral macrophage and neutrophil-mediated innate immunity [51][52][53], also differ significantly between sexes in other disease processes [38,54].…”

Ocular Vascular Diseases: From Retinal Immune Privilege to Inflammation

“…Macrophages present in both experimental and human CNV tissues. Wang et al [124] report that bone-marrow-derived macrophages in bone marrow chimeric mice and local activated microglia quickly move into laser-induced CNV areas. Ccr2 −/− mice exhibited smaller CMV size with a reduced number of ocular-infiltrating macrophages in an experimental CNV mouse model [125,126].…”