CD4+T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS
CD4+T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS
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DOI：
10.1073/pnas.0807419105
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发表时间：
2008-10-07
影响因子：
11.1
通讯作者：
Appel, Stanley H.
中科院分区：
文献类型：
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作者：
Beers, David R.;Henkel, Jenny S.;Appel, Stanley H.
以神经胶质增生和浸润性T细胞为标志的神经炎症是显性遗传性神经退行性疾病的多种模型中的突出病理特征。最近的证据来自转基因小鼠普遍过度表达突变型Cu 2 +/Zn 2+超氧化物歧化酶（mSOD 1），遗传性肌萎缩侧索硬化症（ALS）的慢性神经退行性模型，表明缺乏或减少mSOD 1表达的神经胶质细胞增强运动神经元保护和减缓疾病进展。然而，在mSOD 1转基因小鼠中运动神经元损伤部位存在的T细胞的贡献尚不清楚。在这里，我们表明，当mSOD 1小鼠与缺乏功能性T细胞或CD 4 + T细胞的小鼠一起繁殖时，运动神经元疾病加速，伴随着意外衰减的神经胶质增生的形态标志物，促炎细胞因子和NOX 2的mRNA水平增加，营养因子和神经胶质谷氨酸转运蛋白水平降低。骨髓移植重建小鼠与T细胞，延长生存期，抑制细胞毒性，并恢复神经胶质细胞活化。这些结果首次表明，在慢性神经变性模型中，小胶质细胞和星形胶质细胞的形态学活化不能预测胶质细胞的功能，并且CD 4 + T细胞的存在通过调节胶质细胞的营养/细胞毒性平衡提供支持性神经保护。这些胶质细胞/T细胞相互作用为ALS和可能的其他神经退行性疾病的治疗干预建立了新的靶点。
Neuroinflammation, marked by gliosis and infiltrating T cells, is a prominent pathological feature in diverse models of dominantly inherited neurodegenerative diseases. Recent evidence derived from transgenic mice ubiquitously overexpressing mutant Cu2+/ Zn2+ superoxide dismutase (mSOD1), a chronic neurodegenerative model of inherited amyotrophic lateral sclerosis (ALS), indicates that glia with either a lack of or reduction in mSOD1 expression enhance motoneuron protection and slow disease progression. However, the contribution of T cells that are present at sites of motoneuron injury in mSOD1 transgenic mice is not known. Here we show that when mSOD1 mice were bred with mice lacking functional T cells or CD4+ T cells, motoneuron disease was accelerated, accompanied by unexpected attenuated morphological markers of gliosis, increased mRNA levels for proinflammatory cytokines and NOX2, and decreased levels of trophic factors and glial glutamate transporters. Bone marrow transplants reconstituted mice with T cells, prolonged survival, suppressed cytotoxicity, and restored glial activation. These results demonstrate for the first time in a model of chronic neurodegeneration that morphological activation of microglia and astroglia does not predict glial function, and that the presence of CD4+ T cells provides supportive neuroprotection by modulating the trophic/cytotoxic balance of glia. These glial/T-cell interactions establish a novel target for therapeutic intervention in ALS and possibly other neurodegenerative diseases.