Methyl-CpG Binding Protein 2 Regulates Microglia and Macrophage Gene Expression in Response to Inflammatory Stimuli.
Methyl-CpG Binding Protein 2 Regulates Microglia and Macrophage Gene Expression in Response to Inflammatory Stimuli.
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DOI：
10.1016/j.immuni.2015.03.013
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发表时间：
2015-04-21
期刊：
影响因子：
32.4
通讯作者：
Kipnis J
中科院分区：
文献类型：
--
作者：
Cronk JC;Derecki NC;Ji E;Xu Y;Lampano AE;Smirnov I;Baker W;Norris GT;Marin I;Coddington N;Wolf Y;Turner SD;Aderem A;Klibanov AL;Harris TH;Jung S;Litvak V;Kipnis J
编码表观遗传调节因子甲基-CpG结合蛋白2的MECP2基因突变是瑞特综合征的主要病因，该疾病具有神经系统症状和全身性异常的特征。小胶质细胞功能障碍被认为与疾病发病机制有关，在此我们发现，在Mecp2基因缺失小鼠中，随着疾病进展，小胶质细胞被激活，随后丢失。发现Mecp2在周围巨噬细胞和单核细胞群中表达，其中一些在Mecp2基因缺失小鼠中也会耗竭。RNA测序显示，在Mecp2基因缺失的小胶质细胞和腹膜巨噬细胞中，糖皮质激素和缺氧诱导的转录本表达增加。此外，发现Mecp2在肿瘤坏死因子刺激下调节炎症基因转录。利用Cx3cr1creER在出生后重新表达Mecp2可延长原本Mecp2基因缺失小鼠的寿命。这些数据表明，Mecp2调节小胶质细胞和巨噬细胞对环境刺激的反应性以促进内稳态。组织驻留巨噬细胞功能障碍可能导致瑞特综合征中观察到的全身性病变。
Mutations in MECP2, encoding the epigenetic regulator methyl-CpG-binding protein 2, are the predominant cause of Rett syndrome, a disease characterized by both neurological symptoms and systemic abnormalities. Microglial dysfunction is thought to contribute to disease pathogenesis, and here we found microglia become activated and subsequently lost with disease progression in Mecp2-null mice. Mecp2 was found to be expressed in peripheral macrophage and monocyte populations, several of which also became depleted in Mecp2-null mice. RNA-seq revealed increased expression of glucocorticoid- and hypoxia-induced transcripts in Mecp2-null microglia and peritoneal macrophages. Furthermore, Mecp2 was found to regulate inflammatory gene transcription in response to TNF stimulation. Postnatal re-expression of Mecp2 using Cx3cr1creER increased the lifespan of otherwise Mecp2-null mice. These data suggest Mecp2 regulates microglia and macrophage responsiveness to environmental stimuli to promote homeostasis. Dysfunction of tissue-resident macrophages may contribute to the systemic pathologies observed in Rett syndrome.
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影响因子：
5
作者：
Ning, S.;Pagano, J. S.;Barber, G. N.
通讯作者：
Barber, G. N.
影响因子：
25
作者：
Ballas, Nurit;Lioy, Daniel T.;Grunseich, Christopher;Mandel, Gail
通讯作者：
Mandel, Gail
DOI：
10.1073/pnas.1311141111
发表时间：
2014-03-25
影响因子：
11.1
作者：
Khwaja, Omar S.;Ho, Eugenia;Kaufmann, Walter E.
通讯作者：
Kaufmann, Walter E.
影响因子：
25
作者：
Kierdorf, Katrin;Erny, Daniel;Prinz, Marco
通讯作者：
Prinz, Marco
影响因子：
5.3
作者：
Jung, S;Aliberti, J;Littman, DR
通讯作者：
Littman, DR