Interferon-γ directly induces neurotoxicity through a neuron specific, calcium-permeable complex of IFNγ receptor and AMPA GluR1 receptor
Interferon-γ directly induces neurotoxicity through a neuron specific, calcium-permeable complex of IFNγ receptor and AMPA GluR1 receptor
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DOI：
10.1096/fj.07-099499
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发表时间：
2008-06-01
期刊：
影响因子：
4.8
通讯作者：
Suzumura, Akio
中科院分区：
文献类型：
--
作者：
Mizuno, Tetsuya;Zhang, Guiqin;Suzumura, Akio
干扰素- γ (ifn - γ)是一种促炎细胞因子，在中枢神经系统（CNS）疾病的病理中起关键作用，如多发性硬化症。然而，ifn - γ对神经元细胞的直接作用尚未阐明。我们在这里表明，ifn - γ直接诱导神经元功能障碍，其表现为小鼠皮质神经元中树突头的形成，并增强通过α -氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体介导的谷氨酸神经毒性，而不是通过n -甲基- d -天冬氨酸受体介导的谷氨酸神经毒性。在中枢神经系统中，ifn - γ受体与AMPA受体亚基GluR1形成独特的、神经元特异性的钙渗透性受体复合物。通过该受体复合物，ifn - γ通过JAK1中心点2/ STAT1途径磷酸化丝氨酸845位置的GluR1，增加Ca2+内流和随后的一氧化氮产生，随后减少ATP产生，导致树突头形成。这些发现提供了新的神经元兴奋性毒性机制，这可能发生在中枢神经系统的炎症性和神经退行性疾病中。
Interferon-gamma (IFN-gamma) is a proinflammatory cytokine that plays a pivotal role in pathology of diseases in the central nervous system (CNS), such as multiple sclerosis. However, the direct effect of IFN-gamma on neuronal cells has yet to be elucidated. We show here that IFN-gamma directly induces neuronal dysfunction, which appears as dendritic bead formation in mouse cortical neurons and enhances glutamate neurotoxicity mediated via alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptors but not N-methyl-D-aspartate receptors. In the CNS, IFN-gamma receptor forms a unique, neuron-specific, calcium-permeable receptor complex with AMPA receptor subunit GluR1. Through this receptor complex, IFN-gamma phosphorylates GluR1 at serine 845 position by JAK1 center dot 2/ STAT1 pathway, increases Ca2+ influx and following nitric oxide production, and subsequently decreases ATP production, leading to the dendritic bead formation. These findings provide novel mechanisms of neuronal excitotoxicity, which may occur in both inflammatory and neurodegenerative diseases in the CNS.