Mononuclear phagocytes, immunity, and neural progenitor cells

神经前体细胞(NPC)在一生中持续存在，用于补充神经元和胶质细胞(星形胶质细胞和 少突胶质细胞)。这是通过鼻咽癌的迁移、增殖和分化来促进的。这一过程 神经退行性疾病期间神经发生受到负面影响[包括与HIV-1相关的 痴呆(HAD)、阿尔茨海默氏症和帕金森氏症]。最终结果是死亡或损伤的神经元和 神经胶质细胞的替换速度不会影响疾病的进展。我们假设中枢致病因子 HAD的特点--HIV-1感染和脑激活所致的代谢性脑病 单核巨噬细胞(MP；血管周围和脑内巨噬细胞和小胶质细胞)抑制神经发生 但会促进神经胶质的生成。这种作用可能与MP分泌的肿瘤坏死因子-a和MP介导的 基质细胞衍生因子1(SDF-1)的修饰/降解，它是趋化因子受体CXCR4的配体。 SDF-1和CXCR4之间的异常可以通过改变NPC的活动度来影响神经修复。至少两行 大量证据支持这一观点。首先，CXCR4在人鼻咽癌组织中高表达，并在鼻咽癌组织中起调节作用 迁移。其次，SDF-1在神经胶质细胞激活时被释放，并在脑脊液中升高 曾有过的病人。重要的是，SDF-1(被激活的基质金属蛋白酶-2分解)和肿瘤坏死因子-a/其他促炎因子 细胞因子是由HIV-1感染和激活的MP产生的。因此，这项提案旨在 检测HIV-1感染和激活的MP在神经和神经胶质发生中的作用及其与脑的联系 发炎。我们认为激活的星形胶质细胞产生SDF-1并促进神经发生。这 HIV-1感染和免疫激活的巨噬细胞通过蛋白分解而功能减弱 分泌型SDF-1的修饰/降解导致SDF-1/CXCR4介导的鼻咽癌损伤 迁移。此外，MP分泌的炎性细胞因子，如肿瘤坏死因子-a，可抑制神经发生。 并促进胶质生成，产生不利于中枢神经系统修复的环境。使用人类鼻咽癌 与HIV-1脑炎小鼠相结合的培养系统，该项目将利用模拟 脑MP的IV-1感染与免疫激活这是为了研究中枢神经系统免疫的作用。 对神经发生的反应，就像在HAD期间发生的那样。阐明SDF的作用机制 1/CXCR4和影响神经发生的细胞因子可能为HAD和其他疾病找到新的治疗策略 神经退行性疾病。

Neural progenitor cells (NPC) persist throughout life serving to replenish neurons and glia (astrocytes and' oligodendrocytes). This is facilitated through NPC migration, proliferation and differentiation. This process of neurogenesis is negatively -affected during neurodegenerative disorders [including HIV-1 associated dementia (HAD), Alzheimer's and Parkinson's diseases]. The end result is that dead or injured neurons and glia are not replaced at rates that can affect disease progression. We posit that the central pathogenic feature of HAD, the induction of a metabolic encephalopathy fueled by HIV-1 infected and activated brain mononuclear phagocytes (MP; perivascular and brain macrophages and microglia), inhibits neurogenesis but enhances gliogenesis. This effect may be linked to MP secreted TNF-a and MP mediated modification/degradation of stromal cell-derived factor 1 (SDF-1), a ligand for a chemokine receptor CXCR4. Aberrations between SDF-1 and CXCR4 can affect neural repair by altering NPC mobility. At least two lines of evidence support this notion. First, CXCR4 is highly expressed on human NPC and mediate NPC migration. Second, SDF-1 is released in response to glial activation and is elevated in the cerebrospinal fluid of HAD patients. Importantly, SDF-1 (cleaved by activated matrix metalloproteinase-2) and TNF-a/other proinflammatory cytokines are produced by HIV-1 infected and activated MP. Thus, this proposal seeks to examine the role for HIV-1 infected and activated MP on neuro- and gliogenesis and its links to brain inflammation. We propose activated astrocytes produce SDF-1 and promote neurogenesis. This function is attenuated by HIV-1-infected and immune-activated macrophages through proteolytic modification/degradation of secreted SDF-1, resulting in impairment of SDF-1/CXCR4 mediated NPC migration. Furthermore, MP-secreted inflammatory cytokines, such as TNF-a, inhibits neurogenesis and promotes gliogenesis, generating an environment detrimental to CNS repair. Using a human NPC culture system combined with HIV-1 encephalitis mice, this project will utilize laboratory assays that mimic IV-1 infection and immune activation of brain MP. This is done to investigate the effect of CNS immune response on neurogenesis as it would occur during HAD. Elucidation of the mechanisms by which SDF- 1/CXCR4 and cytokines influence neurogenesis may identify new therapeutic strategies for HAD and other neurodegenerative disorders.