7-Ketocholesterol increases retinal microglial migration, activation, and angiogenicity: a potential pathogenic mechanism underlying age-related macular degeneration.
7-Ketocholesterol increases retinal microglial migration, activation, and angiogenicity: a potential pathogenic mechanism underlying age-related macular degeneration.
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DOI：
10.1038/srep09144
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发表时间：
2015-03-16
影响因子：
4.6
通讯作者：
Wong WT
中科院分区：
文献类型：
--
作者：
Indaram M;Ma W;Zhao L;Fariss RN;Rodriguez IR;Wong WT
年龄相关性黄斑变性（AMD）与脂质和脂质氧化产物的积累，以及外视网膜神经炎症变化和小胶质细胞活化的增加有关。然而，这些因素之间的关系尚不完全清楚。7-酮胆固醇（7KCh）是一种定位于外视网膜的胆固醇氧化产物，具有显著的促炎作用。为了探索7KCh与小胶质细胞激活之间的潜在关系，我们将7KCh和小胶质细胞定位于老年小鼠的外视网膜，并在体外和体内系统中研究7KCh对视网膜小胶质细胞的影响。我们发现视网膜小胶质细胞对7KCh表现出明显的趋化性，并容易内化7KCh。亚致死浓度的7KCh通过NLRP3炎性小体激活导致小胶质细胞激活并极化至促炎M1状态。暴露于7KCh的小胶质细胞减少了神经营养生长因子的表达，但增加了血管生成因子的表达，过渡到更神经毒性和促血管生成表型。最后，在Matrigel-CNV模型中，7kch暴露的小胶质细胞视网膜下移植相对于对照小胶质细胞促进脉络膜新生血管（CNV）。因此，老年视网膜中视网膜小胶质细胞与7KCh的相互作用可能解释了中期AMD中视网膜外脂质积累如何导致神经炎症，最终推动进展为晚期AMD。
Age-related macular degeneration (AMD) has been associated with both accumulation of lipid and lipid oxidative products, as well as increased neuroinflammatory changes and microglial activation in the outer retina. However, the relationships between these factors are incompletely understood. 7-Ketocholesterol (7KCh) is a cholesterol oxidation product localized to the outer retina with prominent pro-inflammatory effects. To explore the potential relationship between 7KCh and microglial activation, we localized 7KCh and microglia to the outer retina of aged mice and investigated 7KCh effects on retinal microglia in both in vitro and in vivo systems. We found that retinal microglia demonstrated a prominent chemotropism to 7KCh and readily internalized 7KCh. Sublethal concentrations of 7KCh resulted in microglial activation and polarization to a pro-inflammatory M1 state via NLRP3 inflammasome activation. Microglia exposed to 7KCh reduced expression of neurotrophic growth factors but increased expression of angiogenic factors, transitioning to a more neurotoxic and pro-angiogenic phenotype. Finally, subretinal transplantation of 7KCh-exposed microglia promoted choroidal neovascularization (CNV) relative to control microglia in a Matrigel-CNV model. The interaction of retinal microglia with 7KCh in the aged retina may thus underlie how outer retinal lipid accumulation in intermediate AMD results in neuroinflammation that ultimately drives progression towards advanced AMD.
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影响因子：
3.7
作者：
Amaral J;Lee JW;Chou J;Campos MM;Rodríguez IR
通讯作者：
Rodríguez IR
影响因子：
1.7
作者：
Hahn, Paul;Ying, Gui-shuang;Dunaief, Joshua L.
通讯作者：
Dunaief, Joshua L.
影响因子：
120.7
作者：
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通讯作者：
Lietman, T
影响因子：
7.8
作者：
Damani MR;Zhao L;Fontainhas AM;Amaral J;Fariss RN;Wong WT
通讯作者：
Wong WT
影响因子：
30.8
作者：
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通讯作者：
Abecasis, Goncalo R.