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Published on: February 12, 2018
Myeloid lineage contributes to pathological choroidal neovascularization formation via SOCS3
Tianxi Wang1, Pingzhu Zhou2, Xuemei Xie3
1Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA.
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 Socs3 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.
Insights
Suppressor of cytokine signaling 3 (SOCS3) in myeloid cells regulates pathological neovascularization in age-related macular degeneration. Enhancing SOCS3 function inhibits neovascular growth and inflammation, offering a potential therapeutic target for vision loss.
Area of Science:
- Ophthalmology
- Immunology
- Vascular Biology
Background:
- Neovascular age-related macular degeneration (nAMD) causes significant vision loss in the elderly due to pathological neovascularization.
- Myeloid lineage cells are increasingly recognized for their role in regulating pathological blood vessel formation.
- The Suppressor of Cytokine Signaling 3 (SOCS3) pathway is implicated in neovascularization processes.
Purpose of the Study:
- To investigate the role of myeloid SOCS3 in the pathogenesis of neovascular age-related macular degeneration (nAMD).
- To elucidate the mechanisms by which myeloid SOCS3 influences pathological choroidal neovascularization (CNV).
Main Methods:
- Utilized a laser-induced CNV mouse model to study nAMD.
- Employed cell lineage reporter mice, bone marrow chimeric mice, and Socs3 knockout/overexpression models.
- Applied immunohistochemistry, confocal microscopy, and choroidal explant co-cultures to analyze myeloid SOCS3 function.
Main Results:
- SOCS3 expression was elevated in myeloid cells within CNV lesions.
- Overexpression of myeloid SOCS3 inhibited CNV formation and reduced inflammatory cell infiltration.
- SOCS3 modulated myeloid cell-driven vascular sprouting in vitro and SOCS3 agonists reduced in vivo CNV.
Conclusions:
- Myeloid lineage cells, regulated by SOCS3, play a critical role in pathological CNV development.
- Targeting myeloid SOCS3 represents a potential therapeutic strategy for nAMD.
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