Institute of Cell Biology and Immunology, University Stuttgart, Stuttgart, Germany.
Glia. 2014 Feb;62(2):272-83. doi: 10.1002/glia.22605. Epub 2013 Dec 6.
Tumor necrosis factor (TNF) and its receptors TNFR1 and TNFR2 have pleiotropic effects in neurodegenerative disorders. For example, while TNFR1 mediates neurodegenerative effects in multiple sclerosis, TNFR2 is protective and contributes to remyelination. The exact mode of TNFR2 action, however, is poorly understood. Here, we show that TNFR2-mediated activation of the PI3K-PKB/Akt pathway in primary astrocytes increased the expression of neuroprotective genes, including that encoding the neurotrophic cytokine leukemia inhibitory factor (LIF). To investigate whether intercellular signaling between TNFR2-stimulated astrocytes and oligodendrocytes plays a role in oligodendrocyte maturation, we established an astrocyte-oligodendrocyte coculture model, composed of primary astrocytes from huTNFR2-transgenic (tgE1335) mice and oligodendrocyte progenitor cells (OPCs) from wild-type mice, capable of differentiating into mature myelinating oligodendrocytes. In this model, selective stimulation of human TNFR2 on astrocytes, promoted differentiation of cocultured OPCs to myelin basic protein-positive mature oligodendrocytes. Addition of LIF neutralizing antibodies inhibited oligodendrocyte differentiation, indicating a crucial role of TNFR2-induced astrocyte derived LIF for oligodendrocyte maturation.
肿瘤坏死因子（TNF）及其受体 TNFR1 和 TNFR2 在神经退行性疾病中具有多种作用。例如，虽然 TNFR1 在多发性硬化症中介导神经退行性作用，但 TNFR2 具有保护作用，并有助于髓鞘再生。然而，TNFR2 的确切作用方式还知之甚少。在这里，我们表明，在原代星形胶质细胞中，TNFR2 介导的 PI3K-PKB/Akt 通路的激活增加了神经保护基因的表达，包括编码神经营养细胞因子白血病抑制因子（LIF）的基因。为了研究 TNFR2 刺激的星形胶质细胞与少突胶质细胞之间的细胞间信号是否在少突胶质细胞成熟中起作用，我们建立了一个星形胶质细胞-少突胶质细胞共培养模型，由 huTNFR2 转基因（tgE1335）小鼠的原代星形胶质细胞和野生型小鼠的少突胶质前体细胞（OPC）组成，能够分化为成熟的髓鞘形成少突胶质细胞。在该模型中，对星形胶质细胞的人 TNFR2 的选择性刺激促进了共培养的 OPC 分化为髓鞘碱性蛋白阳性的成熟少突胶质细胞。添加 LIF 中和抗体抑制了少突胶质细胞分化，表明 TNFR2 诱导的星形胶质细胞衍生的 LIF 对少突胶质细胞成熟具有关键作用。
