CXCL8-mediated glial cross-talk and neuroprotection in HIV-1 Dementia

目前，全球有近3500万艾滋病毒感染者。HIV-1相关性痴呆(HAD) 与轻微的神经认知障碍和无症状的神经认知障碍一起构成艾滋病毒- 相关神经认知障碍(手)。与轻度HIV脑炎相关的炎症 显示炎症区域存在激活的小胶质细胞、反应性星形胶质细胞增生症和神经元损伤。几个 几年前，我们开始对与神经胶质细胞激活相关的潜在机制进行新的研究 对神经艾滋病的贡献。在初步实验中使用原代人神经胶质细胞，CXCL8 在激活的星形胶质细胞和其他神经细胞中上调的关键分子中。重要的是，CXCL8是 HIV-1相关神经毒素对培养的人类神经元的神经保护作用。它的生物学相关性 观察结果进一步证实，感染HIV-1的脑组织显示CXCL8水平更高， 与年龄匹配的对照组相比。我们认为CXCL8在这一过程中起着关键的调节作用。 HIV-1中枢神经系统感染中的细胞间相互作用小胶质细胞感染和激活导致血管内皮生长因子上调 IL-1。IL-1β是星形胶质细胞的典型炎症刺激因子，可促进星形胶质细胞产生CXCL8。 中枢神经系统。CXCL8进一步招募小胶质细胞，并调节小胶质细胞激活和HIV-1感染。加在一起， 最终，这些事件可能导致CXCL8介导的直接或间接神经保护。为此，我们将 回答以下具体问题：HAD中激活的星形胶质细胞中CXCL8是如何调节的？ 有机制牵涉其中吗？(目的1)胶质细胞CXCL8如何调节小胶质细胞的募集、激活和 感染？(目的2)CXCL8是如何在HAD过程中调节神经元存活和/或功能的？ (目标3) 在目标1中，将利用人脑组织样本和原代人类神经细胞来描绘 并鉴定HAD中CXCL8的细胞来源。原代人类神经细胞将是 暴露于HAD特异性刺激和CXCL8调节将被评估。细胞内信号转导途径 参与IL-8的调节，特别是在星形胶质细胞中，将研究核因子-B、p38MAPK和/或SHP2。的作用 CXCL8介导激活的星形胶质细胞与小胶质细胞之间的细胞间相互作用 Aim 2将评估小胶质细胞的激活、募集和HIV-1感染。CXCL8的机制 Akt/PKB、ERK1/2、Bcl2和Bax特异性的神经保护及其信号转导 肿瘤坏死因子受体在这些神经保护事件中的作用将使用原代人神经元进行研究。 目的3.综上所述，本申请中提出的研究将提供关于CXCL8介导的新数据 胶质细胞串扰和神经发病机制，并导致对胶质细胞炎症调控的新见解 既有基础意义又有临床意义的反应。

Currently, almost 35 million people live with HIV-1 infection worldwide. HIV-1-associated dementia (HAD) along with mild neurocognitive disorder and asymptomatic neurocognitive impairment comprises the HIV- associated neurocognitive disorder (HAND). Inflammation associated with milder forms of HIV encephalitis shows presence of activated microglia, reactive astrogliosis and neuronal injury in areas of inflammation. A few years ago, we began novel investigations into the potential mechanisms associated with glial activation & their contribution in neuro-AIDS. Primary human glial cells were used in preliminary experiments and CXCL8 was among the key molecules upregulated in activated astrocytes and other neural cells. Importantly, CXCL8 was neuroprotective in cultured human neurons exposed to HIV-1-related neurotoxins. Biological relevance of this observation was further confirmed as HIV-1-infected brain tissues demonstrated greater CXCL8 levels as compared to age-matched controls. We propose that CXCL8 plays a key regulatory role in the intercellular interactions in HIV-1 CNS infection. Microglial infection and activation leads to upregulation of IL-1¿. IL-1¿, a prototypical inflammatory stimulus for astrocytes, enhances CXCL8 production by astrocytes in CNS. CXCL8 further recruits microglia and regulates microglial activation and HIV-1 infection. Taken together, ultimately these events may lead to CXCL8-mediated direct or indirect neuroprotection. To these ends, we will address the following specific questions: How is CXCL8 regulated in activated astrocytes in HAD and what mechanisms are involved? (Aim 1) How does glial CXCL8 regulate microglial recruitment, activation and infection? (Aim 2) How does CXCL8 regulate neuronal survival and/or function during the process of HAD? (Aim 3) In Aim 1, human brain tissue specimens and primary human neural cells will be utilized to delineate CXCL8 profiles and to identify the cellular sources for CXCL8 in HAD. Primary human neural cells will be exposed to HAD-specific stimuli and CXCL8 regulation will be evaluated. The intracellular signaling pathways involved in IL-8 regulation, specifically, NF-¿B, p38MAPK and/or SHP2 will be studied in astrocytes. The role of intercellular interactions between activated astrocytes and microglia via CXCL8-mediated in regulation of microglial activation, recruitment and HIV-1 infection will be evaluated in Aim 2. The mechanisms of CXCL8 neuroprotection and the ensuing signal transduction specifically through Akt/PKB, ERK1/2, Bcl-2 and Bax and the role of TNF receptors in these neuroprotective events will be investigated using primary human neurons in Aim 3. Taken together, the studies proposed in this application will provide novel data about CXCL8-mediated glial cross-talk and neuropathogenesis and lead to novel insights into regulation of glial inflammatory responses that have both basic and clinical significance.