Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, China.
Exp Neurol. 2012 Sep;237(1):147-52. doi: 10.1016/j.expneurol.2012.06.011. Epub 2012 Jun 23.
Neuroinflammation is a prominent pathological feature in the spinal cords of patients with amyotrophic lateral sclerosis (ALS), as well as in transgenic mouse models of inherited ALS, and is characterized by activated microglia. Earlier studies showed that activated microglia play important roles in both motoneuron protection and injury. More recent studies investigating the pathoprogression of disease in ALS mice have demonstrated that the in vivo activation states of microglia, including their anti- versus pro-inflammatory responses, are best characterized as a continuum between two extreme activation states which are represented as a neuroprotective M2 (alternatively-activated) phenotypic state or an injurious/toxic M1 (classically-activated) state; a more complete understanding and determination the temporal transformation of microglia activation states in the ALS disease pathoprogression is therefore warranted. In the current study, we demonstrated a phenotypic and functional transformation of adult ALS mice microglia that overexpress mutant superoxide dismutase (mSOD1). mSOD1 microglia isolated from ALS mice at disease onset expressed higher levels of Ym1, CD163 and BDNF (markers of M2) mRNA and lower levels of Nox2 (a marker of M1) mRNA compared with mSOD1 microglia isolated from ALS mice at end-stage disease. More importantly, when co-cultured with motoneurons, these mSOD1 M2 microglia were neuroprotective and enhanced motoneuron survival than similarly co-cultured mSOD1 M1 microglia; end-stage mSOD1 M1 microglia were toxic to motoneurons. Our study documents that adult microglia isolated from ALS mice at disease onset have an M2 phenotype and protect motoneurons whereas microglia isolated from end-stage disease ALS mice have adopted an M1 phenotype and are neurotoxic supporting the dual phenotypes of microglia and their transformation during disease pathoprogression in these mice. Thus, harnessing the neuroprotective potential of microglia may provide novel avenues for ALS therapies.
神经炎症是肌萎缩侧索硬化症（ALS）患者脊髓以及遗传性 ALS 转基因小鼠模型中的一个显著病理特征，其特征为激活的小胶质细胞。早期研究表明，激活的小胶质细胞在运动神经元的保护和损伤中都发挥着重要作用。最近研究 ALS 小鼠疾病进展的研究表明，小胶质细胞的体内激活状态，包括其抗炎和促炎反应，最好被描述为两种极端激活状态之间的连续体，这两种状态分别代表一种具有神经保护作用的 M2（替代性激活）表型状态或具有损伤/毒性的 M1（经典激活）状态；因此，更全面地了解和确定 ALS 疾病进展中小胶质细胞激活状态的时间转化是有必要的。在本研究中，我们证明了过表达突变超氧化物歧化酶（mSOD1）的成年 ALS 小鼠小胶质细胞的表型和功能发生了转化。与晚期疾病来源的 mSOD1 小胶质细胞相比，疾病早期分离的 ALS 小鼠 mSOD1 小胶质细胞表达更高水平的 Ym1、CD163 和 BDNF（M2 标志物）mRNA，以及更低水平的 Nox2（M1 标志物）mRNA。更重要的是，当与运动神经元共培养时，这些 mSOD1 M2 小胶质细胞具有神经保护作用，并增强了与 mSOD1 M1 小胶质细胞共培养的运动神经元的存活率；晚期 mSOD1 M1 小胶质细胞对运动神经元有毒性。我们的研究表明，从疾病早期的 ALS 小鼠中分离出的成年小胶质细胞具有 M2 表型并保护运动神经元，而从晚期疾病的 ALS 小鼠中分离出的小胶质细胞具有 M1 表型并具有神经毒性，支持了小胶质细胞的双表型及其在这些小鼠疾病进展中的转化。因此，利用小胶质细胞的神经保护潜力可能为 ALS 治疗提供新途径。
