Key Role of Microglial Matrix Metalloproteinases in Choroidal Neovascularization

Frontiers in Cellular Neuroscience

Kyoungho Suk¹  Jong-Heon Kim¹  Ryoji Yanai²  In-kyu Lee³  Juhee Kim⁶  Ji Yeon Do⁶  Jung Yi Lee⁷  Dong Ho Park⁸ 

[1] Brain Science and Engineering Institute, Kyungpook National University, Daegu, South Korea;D Center, JD Bioscience Inc., Gwangju, South Korea;Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea;Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube, Japan;Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, South Korea;Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, South Korea;;R&Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, South Korea;

关键词: age-related macular degeneration (AMD);    choroidal neovascluarization;    matrix metalloproteinase;    microglia;    aqueous humor;   

DOI  :  10.3389/fncel.2021.638098

来源: DOAJ

【 摘 要 】

Age-related macular degeneration (AMD), especially neovascular AMD with choroidal neovascularization (CNV), is the leading cause of blindness in the elderly. Although matrix metalloproteinases (MMPs) are involved in pathological ocular angiogenesis, including CNV, the cellular origin of MMPs in AMD remains unknown. The present study investigated the role of microglial MMPs in CNV. MMP activities were analyzed by gelatin zymography in aqueous humor samples from patients with CNV and laser-induced CNV mice. Active MMP-9 was increased in the aqueous humor samples from neovascular AMD patients compared with control subjects. In the retinal pigment epithelium (RPE)/choroid from CNV mice, active MMP-9 increased, beginning 1 h post-CNV induction, and remained upregulated until Day 7. In RPE/choroid from CNV mice, active MMP-9 was suppressed by minocycline, a known microglial inhibitor, at 6 h and 1-day post-CNV induction. Flow cytometry revealed that the proportion of activated microglia increased very early, beginning at 1 h post-CNV induction, and was maintained until Day 7. Similarly, immunohistochemistry revealed increased microglial activation and MMP-9 expression on CNV lesions at 6 h and 1-day post-CNV induction. SB-3CT, an MMP inhibitor, decreased vascular leakage and lesion size in laser-induced CNV mice. These findings indicated nearly immediate recruitment of activated microglia and very early MMP-9 activation in the RPE/choroid. The present study newly identified a potential role for early microglial MMP-9 expression in CNV, and furthermore that modulating microglial MMP expression is a novel putative therapeutic for CNV.

【 授权许可】

Unknown