Walker Douglas G, Lue Lih-Fen
Laboratory of Neuroinflammation, Banner Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ, 85351, USA.
Alzheimers Res Ther. 2015 Aug 19;7(1):56. doi: 10.1186/s13195-015-0139-9.
Inflammatory responses in the brain, which can be demonstrated by changes in properties of microglia, the brain-resident macrophages, are a common feature of human neurodegenerative diseases. Different monocyte/macrophage phenotypes have been defined by changes in expression of cytokines, receptors and other markers as a response to different classes of stimuli. Monocytes, macrophages and microglia can have a range of phenotypes with associated properties depending on their microenvironment. Macrophage/microglia polarization states have been defined as classical activation (M1), alternative activation (M2a), type II alternative activation (M2b) or acquired deactivation (M2c). Available markers for identifying microglial phenotypes in human brains are still limited; those available provide incomplete information on the functions or polarization states of microglia observed in tissues from diseases such as Alzheimer's disease, Parkinson's disease and multiple sclerosis. The most widely used marker to describe activated microglia in human brains, particularly diseased brains, has been HLA-DR, the major histocompatibility complex II protein. HLA-DR-positive microglia can have a wide range of activation morphologies that are affected not only by disease pathology, but also by their differentiation states and brain regions. Two other widely used markers to identify microglia in human brains are ionized calcium binding adaptor molecule-1 and CD68. Although their expression changes in diseased brains, these markers do not show specificity for different phenotypes. Over the years there have been studies with additional markers that attempt to further define microglial properties, particularly in Alzheimer's disease brains. Most studies have employed immunohistochemical techniques to identify microglia in tissue sections, but recent advances in this field have allowed gene expression profiling of microglia upon immediate isolation from brains. We will review which markers might better define different activation phenotypes of microglia in human brains and whether they fit into current microglial polarization schemes.
大脑中的炎症反应是人类神经退行性疾病的一个常见特征，这可以通过脑内常驻巨噬细胞——小胶质细胞的特性变化来证明。不同的单核细胞/巨噬细胞表型是由细胞因子、受体和其他标志物表达的变化所定义的，这些变化是对不同类型刺激的反应。单核细胞、巨噬细胞和小胶质细胞可以具有一系列取决于其微环境的表型及相关特性。巨噬细胞/小胶质细胞的极化状态已被定义为经典激活（M1）、替代激活（M2a）、II型替代激活（M2b）或获得性失活（M2c）。用于识别人类大脑中小胶质细胞表型的现有标志物仍然有限；现有的标志物提供的关于在阿尔茨海默病、帕金森病和多发性硬化症等疾病组织中观察到的小胶质细胞功能或极化状态的信息并不完整。在人类大脑中，尤其是患病大脑中，描述活化小胶质细胞最广泛使用的标志物是主要组织相容性复合体II类蛋白HLA-DR。HLA-DR阳性小胶质细胞可以具有广泛的激活形态，这些形态不仅受疾病病理学影响，还受其分化状态和脑区的影响。另外两个广泛用于识别人类大脑中小胶质细胞的标志物是离子钙结合衔接分子1和CD68。尽管它们在患病大脑中的表达会发生变化，但这些标志物并未显示出对不同表型的特异性。多年来，有一些研究使用了其他标志物，试图进一步定义小胶质细胞的特性，特别是在阿尔茨海默病大脑中。大多数研究采用免疫组织化学技术在组织切片中识别小胶质细胞，但该领域的最新进展使得能够在从小脑立即分离后对小胶质细胞进行基因表达谱分析。我们将综述哪些标志物可能更好地定义人类大脑中小胶质细胞的不同激活表型，以及它们是否符合当前的小胶质细胞极化模式。
