Mononuclear phagocytes, immunity, and neural progenitor cells

神经祖细胞（NPC）在整个生命中持续存在，用于补充神经元和神经胶质（星形胶质细胞和胶质细胞）。 少突胶质细胞）。这是通过NPC迁移，增殖和分化促进的。的过程 在神经退行性疾病[包括HIV-1相关的 痴呆（HAD）、阿尔茨海默病和帕金森病]。最终的结果是死亡或受伤的神经元， 神经胶质细胞不会以影响疾病进展的速率被替换。我们认为，中央致病 HAD的特征，即由HIV-1感染和激活的大脑引起的代谢性脑病的诱导 单核吞噬细胞（MP;血管周围和脑巨噬细胞和小胶质细胞），抑制神经发生 但增强神经胶质生成。这种作用可能与MP分泌TNF-α和MP介导的TNF-α的表达有关。 基质细胞衍生因子1（SDF-1），趋化因子受体CXCR 4的配体的修饰/降解。 SDF-1和CXCR 4之间的畸变可以通过改变NPC移动性来影响神经修复。至少两条线 证据支持这一观点。首先，CXCR 4在人NPC中高表达，并介导NPC的发生， 迁移第二，SDF-1响应于胶质细胞活化而释放，并且在脑脊液中升高 的患者。重要的是，SDF-1（被活化的基质金属蛋白酶-2切割）和TNF-α/其他促炎性因子（TNF-α/ 细胞因子由HIV-1感染和活化的MP产生。因此，这项建议旨在 研究HIV-1感染和激活的MP对神经元和胶质细胞生成的作用及其与大脑的联系 炎症我们建议活化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水解 分泌的SDF-1的修饰/降解，导致SDF-1/CXCR 4介导的NPC受损 迁移此外，MP分泌的炎性细胞因子如TNF-α抑制神经发生， 并促进神经胶质生成，产生对CNS修复有害的环境。使用人类NPC 培养系统结合HIV-1脑炎小鼠，该项目将利用实验室检测，模拟 IV-1感染与脑MP的免疫激活。这是为了研究CNS免疫的影响， 在HAD期间会发生的神经发生反应。阐明了SDF- 1/CXCR 4和细胞因子影响神经发生可能为HAD和其他疾病确定新的治疗策略。 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.