USP18 lack in microglia causes destructive interferonopathy of the mouse brain
USP18 lack in microglia causes destructive interferonopathy of the mouse brain
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DOI：
10.15252/embj.201490791
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发表时间：
2015-06-12
期刊：
影响因子：
11.4
通讯作者：
Prinz, Marco
中科院分区：
文献类型：
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作者：
Goldmann, Tobias;Zeller, Nicolas;Prinz, Marco
小胶质细胞是中枢神经系统（CNS）的组织巨噬细胞，其控制组织稳态。小胶质细胞失调被认为是一组神经精神疾病、神经退行性疾病和神经炎性疾病（称为“小胶质细胞病”）的病因。然而，小胶质细胞中的细胞内刺激机制是如何控制的知之甚少。在这里，我们确定了泛素特异性蛋白酶（Usp）18在白色物质小胶质细胞，基本上有助于小胶质细胞的静止。我们进一步发现，小胶质细胞Usp18负调节Stat1的激活和干扰素诱导基因的伴随诱导，从而终止IFN信号。Usp18介导的控制是独立于其催化活性，而是需要与Ifnar2的相互作用。此外，Ifnar 1的缺乏恢复了小胶质细胞的活化，表明在非疾病条件下需要由Usp 18负控制的紧张性IFN信号。这些结果确定了Usp18作为小胶质细胞活化的关键负调节因子，并证明了Usp18通过调节Ifnar通路对小胶质细胞功能的保护作用。这些发现将Usp18确定为一种预防破坏性小胶质细胞病的新分子。
Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called "microgliopathies". However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. Here, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence. We further found that microglial Usp18 negatively regulates the activation of Stat1 and concomitant induction of interferon-induced genes, thereby terminating IFN signaling. The Usp18-mediated control was independent from its catalytic activity but instead required the interaction with Ifnar2. Additionally, the absence of Ifnar1 restored microglial activation, indicating a tonic IFN signal which needs to be negatively controlled by Usp18 under non-diseased conditions. These results identify Usp18 as a critical negative regulator of microglia activation and demonstrate a protective role of Usp18 for microglia function by regulating the Ifnar pathway. The findings establish Usp18 as a new molecule preventing destructive microgliopathy.