Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY.
Department of Psychiatry, New York University Langone Medical Center, New York, NY.
Ann Neurol. 2018 Feb;83(2):406-417. doi: 10.1002/ana.25160. Epub 2018 Feb 10.
CD16 /CD163 macrophages (MΦs) and microglia accumulate in the brains of patients with human immunodeficiency virus (HIV) encephalitis (HIVE), a neuropathological correlate of the most severe form of HIV-associated neurocognitive disorders, HIV-associated dementia. Recently, we found that some parenchymal microglia in brain of HIV subjects without encephalitis (HIV/noE) but with varying degrees of neurocognitive impairment express CD16 and CD163, even in the absence of detectable virus production. To further our understanding of microglial activation in HIV, we investigated expression of specific genes by profiling parenchymal microglia from archival brain tissue of patients with HIVE and HIV/noE, and HIV controls.
Single-population microarray analyses were performed on ∼2,500 laser capture microdissected CD163 , CD16 , or CD68 MΦs/microglia per case, using terminal continuation RNA amplification and a custom-designed array platform.
Several classes of microglial transcripts in HIVE and HIV/noE were altered, relative to HIV subjects, including factors related to cell stress, immune activation, and apoptosis. Additionally, several neurotrophic factors were reduced in HIV infection, suggesting an additional mechanism of neuropathogenesis. The majority of transcripts altered in HIVE displayed intermediate changes in HIV/noE.
Our results support the notion that microglia contribute to the maintenance of brain homeostasis and their potential loss of function in the context of chronic inflammation contributes to neuropathogenesis. Furthermore, they indicate the utility of profiling MΦs/microglia to increase our understanding of microglia function, as well as to ascertain alterations in specific pathways, genes, and potentially, encoded proteins that may be amenable to targeted treatment modalities in diseases affecting the brain. Ann Neurol 2018;83:406-417.
CD16/CD163 巨噬细胞（MΦ）和小胶质细胞在人类免疫缺陷病毒（HIV）脑炎（HIVE）患者的大脑中积累，这是 HIV 相关神经认知障碍最严重形式 HIV 相关痴呆的神经病理学相关。最近，我们发现，HIV 患者（HIV/noE）大脑中没有脑炎，但有不同程度的神经认知障碍的一些实质小胶质细胞表达 CD16 和 CD163，即使没有检测到可检测的病毒产生。为了进一步了解 HIV 中小胶质细胞的激活，我们通过对 HIVE 和 HIV/noE 患者和 HIV 对照患者的存档脑组织中实质小胶质细胞进行基因表达谱分析，研究了特定基因的表达。
对每个病例约 2500 个激光捕获微解剖 CD163、CD16 或 CD68 MΦ/小胶质细胞进行单细胞群体微阵列分析，使用末端延续 RNA 扩增和定制设计的阵列平台。
与 HIV 患者相比，HIVE 和 HIV/noE 中的几类小胶质细胞转录物发生了改变，包括与细胞应激、免疫激活和细胞凋亡相关的因子。此外，几种神经营养因子在 HIV 感染中减少，提示存在另一种神经发病机制。在 HIVE 中改变的大多数转录物在 HIV/noE 中显示出中间变化。
我们的研究结果支持这样的观点，即小胶质细胞有助于维持大脑内稳态，并且它们在慢性炎症背景下潜在的功能丧失可能导致神经发病机制。此外，它们表明分析 MΦ/小胶质细胞可用于增加我们对小胶质细胞功能的理解，以及确定特定途径、基因和潜在的编码蛋白的改变，这些改变可能适合针对影响大脑的疾病的靶向治疗模式。Ann Neurol 2018;83:406-417。
