PRODUCTION OF CCL7 BY ASTROCYTES: SIV NEUROINVASION AND AIDS ENCEPHALITIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 单核/巨噬细胞和激活的淋巴细胞通过正常大脑进行运输，这种运输在炎症性条件下增加，如艾滋病毒脑炎(HIVE)。蜂窝的部分特征是巨噬细胞在血管周围堆积。这一过程中最早的事件很少被理解，很难或不可能在人类身上解决。SIV感染的神经艾滋病猕猴模型显示单核细胞在疾病早期迁移到大脑，与SIV病毒血症的峰值一致。启动单个核细胞向中枢神经系统迁移增加的趋化信号尚未被描述。在这里，我们将星形胶质细胞描述为趋化因子的来源，以促进基础水平的单核细胞向中枢神经系统的转运，而CCL7产量的增加可能是导致神经艾滋病贩运增加的原因。我们之前已经发表了补充的体内工作，证明了SIV感染的猕猴大脑中存在MCP-3/CCL7(和其他趋化因子)。在这里，我们证明了MCP-3/CCL7是由星形胶质细胞产生的一种重要的趋化因子，CCL7负责单核细胞募集的基础水平，CCL7的产生被肿瘤坏死因子迅速增加，因此可能在启动SIV/HIV的神经侵袭中发挥关键作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Monocyte/macrophages and activated lymphocytes traffic through normal brain, and this trafficking is increased in inflammatory conditions such as HIV encephalitis (HIVE). HIVE is characterized in part by perivascular accumulations of macrophages. The earliest events in this process are poorly understood and difficult or impossible to address in humans. The SIV-infected macaque model of neuroAIDS has demonstrated migration of monocytes into the brain early in disease, coincident with peak SIV viremia. The chemotactic signals that initiate the increased emigration of mononuclear cells into the CNS have not been described. Here we describe astrocytes as a source of chemokines to facilitate basal levels of monocyte trafficking to CNS and that increased CCL7 production is probably responsible for initiating the increased trafficking in neuroAIDS. We have previously published complementary in vivo work demonstrating the presence of MCP-3/CCL7 (and other chemokines) within the brain of SIV-infected macaques. Here we demonstrate that MCP-3/CCL7 is a significant chemokine produced by astrocytes, that CCL7 is responsible for basal levels of monocyte recruitment and that production of CCL7 is rapidly increased by TNF and thus likely plays a critical role in initiating neuroinvasion by SIV/HIV.