Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS.
Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS.
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DOI：
10.1016/j.expneurol.2012.06.011
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发表时间：
2012-09
影响因子：
5.3
通讯作者：
Appel, Stanley H.
中科院分区：
文献类型：
--
作者：
Liao, Bing;Zhao, Weihua;Beers, David R.;Henkel, Jenny S.;Appel, Stanley H.
神经炎症是肌萎缩侧索硬化症（ALS）患者脊髓中的一个突出病理特征，也是遗传性ALS的转基因小鼠模型中的一个突出病理特征，其特征在于活化的小胶质细胞。早期研究表明，激活的小胶质细胞在运动神经元保护和损伤中起重要作用。最近研究ALS小鼠疾病病理进展的研究表明，小胶质细胞的体内激活状态，包括其抗炎反应与促炎反应，最好表征为两种极端激活状态之间的连续体，其表示为神经保护性M2（交替激活）表型状态或有害/毒性M1因此，需要更全面地理解和确定ALS疾病病理进展中小胶质细胞激活状态的时间转化。在目前的研究中，我们证明了一个表型和功能的转化成年ALS小鼠小胶质细胞过表达突变型超氧化物歧化酶（mSOD 1）。与从终末期疾病的ALS小鼠中分离的mSOD 1小胶质细胞相比，从疾病发作的ALS小鼠中分离的mSOD 1小胶质细胞表达较高水平的Ym 1、CD 163和BDNF（M2的标志物）mRNA和较低水平的Nox 2（M1的标志物）mRNA。更重要的是，当与运动神经元共培养时，这些mSOD 1 M2小胶质细胞具有神经保护作用，并且比类似的共培养mSOD 1 M1小胶质细胞增强运动神经元存活;终末期mSOD 1 M1小胶质细胞对运动神经元有毒。我们的研究证明，从ALS小鼠中分离的成年小胶质细胞在疾病发作时具有M2表型并保护运动神经元，而从终末期疾病ALS小鼠中分离的小胶质细胞具有M1表型并具有神经毒性，支持这些小鼠中小胶质细胞的双重表型及其在疾病病理进展期间的转化。因此，利用小胶质细胞的神经保护潜力可能为ALS治疗提供新的途径。
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 neuro-protective 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 pheno-types 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.
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DOI：
10.1093/brain/awr074
发表时间：
2011-05
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Beers DR;Henkel JS;Zhao W;Wang J;Huang A;Wen S;Liao B;Appel SH
通讯作者：
Appel SH
影响因子：
5.3
作者：
Le, WD;Rowe, D;Appel, SH
通讯作者：
Appel, SH
影响因子：
4.4
作者：
Aloisi, F;De Simone, R;Adorini, L
通讯作者：
Adorini, L
影响因子：
15.1
作者：
Serpe, CJ;Byram, SC;Jones, KJ
通讯作者：
Jones, KJ
影响因子：
4.7
作者：
Xiao, Qin;Zhao, Weihua;Appel, Stanley H.
通讯作者：
Appel, Stanley H.