Insulin-Like Growth Factor 2 Receptor Is an IFNγ-Inducible Microglial Protein that Facilitates Intracellular HIV Replication
Insulin-Like Growth Factor 2 Receptor Is an IFNγ-Inducible Microglial Protein that Facilitates Intracellular HIV Replication
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DOI：
10.2353/ajpath.2010.100399
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发表时间：
2010-11-01
影响因子：
6
通讯作者：
Lee, Sunhee C.
中科院分区：
文献类型：
--
作者：
Suh, Hyeon-Sook;Cosenza-Nashat, Melissa;Lee, Sunhee C.
胰岛素样生长因子2受体（IGF2R），也被称为阳离子非依赖性甘露糖6-磷酸（M6P）受体，是一种定位于反式高尔基区的跨膜糖蛋白，参与将携带M6P的酶和IGF2靶向溶酶体腔室。在发育过程中，IGF2R在清除组织和血液中多余的生长因子方面起着至关重要的作用。由于Igf2r基因整体敲除的围产期致命性，Igf2r在成人中的功能，特别是在中枢神经系统中的功能尚不清楚。我们观察到IGF2R在HIV脑炎患者大脑的小胶质结节中高度表达。在体外，在几种细胞因子和TLR配体中，IFN γ唯一地增强了小胶质细胞IGF2R的表达。此外，在几种体外HIV感染模型中，包括人和小鼠小胶质细胞、巨噬细胞和非巨噬细胞，IGF2R被反复证明是HIV感染的阳性调节因子。IGF2R RNAi也下调hiv感染的人小胶质细胞中IP-10趋化因子的产生。在小鼠脑内注射VSVg env HIV诱导神经元中HIV p24的表达，这是成人脑中唯一正常表达IGF2R的细胞类型。我们的研究结果表明，IGF2R作为一种可诱导的小胶质蛋白参与调节HIV和趋化因子的表达。具有Csf1r驱动的Igf2r敲除的小鼠应该对巨噬细胞特异性Igf2r功能的研究有用。（中华病理学杂志，2010,177:2446-2458;DOI: 10.2353/ajpath.2010.100399）
Insulin-like growth factor 2 receptor (IGF2R), also known as cation-independent mannose 6-phosphate (M6P) receptor, is a transmembrane glycoprotein localized in the trans-Golgi region and is involved in targeting both M6P-bearing enzymes and IGF2 to the lysosomal compartment. During development, IGF2R plays a crucial role in removing excess growth factors from both tissue and blood. Due to the perinatal lethality of the global Igf2r knockout, the function of IGF2R in adults, particularly in the CNS, is not known. We made a novel observation that IGF2R is highly expressed in microglial nodules in human brains with HIV encephalitis. In vitro, microglial IGF2R expression was uniquely enhanced by IFN gamma among the several cytokines and TLR ligands examined. Furthermore, in several in vitro models of HIV infection, including human and murine microglia, macrophages, and nonmacrophage cells, IGF2R is repeatedly shown to be a positive regulator of HIV infection. IGF2R RNAi also down-regulated the production of the IP-10 chemokine in HIV-infected human microglia. Injection of VSVg env HIV into mouse brain induced HIV p24 expression in neurons, the only cell type normally expressing IGF2R in the adult brain. Our results demonstrate a novel role for IGF2R as an inducible microglial protein involved in regulation of HIV and chemokine expression. Mice with the Csf1r- driven Igf2r knockout should be useful for the investigation of macrophage-specific IGF2R function. (Am J Pathol 2010, 177:2446-2458; DOI: 10.2353/ajpath.2010.100399)