Identification and validation of Ifit1 as an important innate immune bottleneck.
Identification and validation of Ifit1 as an important innate immune bottleneck.
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DOI：
10.1371/journal.pone.0036465
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Stenzel-Poore MP
中科院分区：
文献类型：
--
作者：
McDermott JE;Vartanian KB;Mitchell H;Stevens SL;Sanfilippo A;Stenzel-Poore MP
先天免疫系统在许多不同的过程中发挥着重要作用。最重要的是，先天免疫是对病原体入侵的第一反应，触发早期防御反应并招募适应性免疫系统。先天免疫系统也会对组织损伤产生的内源性损伤信号做出反应。近年来，研究发现先天免疫通过激活主要的先天免疫受体Toll样受体(TLRs)在缺血性卒中的神经保护中发挥重要作用。使用来自小鼠和小鼠巨噬细胞研究的几个大规模转录数据集，我们确定了预测在控制TLR激活启动的天然免疫过程中重要的靶点。根据基因表达模式之间的统计关联，在网络中，靶标被确定为具有高度介数中心性的基因，即所谓的瓶颈。在每个被调查的数据集中都发现了一小部分假定的瓶颈，包括干扰素刺激基因(Ifit1、Ifi47、Tgtp和Oas12)以及未表现出免疫反应特征的基因(Axud1和Ppp1r15a)。我们进一步在小鼠巨噬细胞中验证了其中一个靶点，Ifit1，表明沉默它可以通过未知的直接或间接机制抑制脂多糖(LPS)介导的TLR4激活所预测的下游基因的诱导。我们的研究证明了网络分析在识别与先天性免疫功能相关的有趣靶点方面的有效性，并强调了Ifit1可以对下游基因起到积极的调节作用。
The innate immune system plays important roles in a number of disparate processes. Foremost, innate immunity is a first responder to invasion by pathogens and triggers early defensive responses and recruits the adaptive immune system. The innate immune system also responds to endogenous damage signals that arise from tissue injury. Recently it has been found that innate immunity plays an important role in neuroprotection against ischemic stroke through the activation of the primary innate immune receptors, Toll-like receptors (TLRs). Using several large-scale transcriptomic data sets from mouse and mouse macrophage studies we identified targets predicted to be important in controlling innate immune processes initiated by TLR activation. Targets were identified as genes with high betweenness centrality, so-called bottlenecks, in networks inferred from statistical associations between gene expression patterns. A small set of putative bottlenecks were identified in each of the data sets investigated including interferon-stimulated genes (Ifit1, Ifi47, Tgtp and Oasl2) as well as genes uncharacterized in immune responses (Axud1 and Ppp1r15a). We further validated one of these targets, Ifit1, in mouse macrophages by showing that silencing it suppresses induction of predicted downstream genes by lipopolysaccharide (LPS)-mediated TLR4 activation through an unknown direct or indirect mechanism. Our study demonstrates the utility of network analysis for identification of interesting targets related to innate immune function, and highlights that Ifit1 can exert a positive regulatory effect on downstream genes.
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影响因子：
6.3
作者：
McCabe, Christopher;White, Fiona;Macrae, I. Mhairi
通讯作者：
Macrae, I. Mhairi
影响因子：
5.4
作者：
Minami, Kahori;Tambe, Yukihiro;Inoue, Hirokazu
通讯作者：
Inoue, Hirokazu
DOI：
10.1126/science.1179050
发表时间：
2009-10-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Amit I;Garber M;Chevrier N;Leite AP;Donner Y;Eisenhaure T;Guttman M;Grenier JK;Li W;Zuk O;Schubert LA;Birditt B;Shay T;Goren A;Zhang X;Smith Z;Deering R;McDonald RC;Cabili M;Bernstein BE;Rinn JL;Meissner A;Root DE;Hacohen N;Regev A
通讯作者：
Regev A
DOI：
10.1196/annals.1299.042
发表时间：
2003-01-01
期刊：
APOPTOSIS: FROM SIGNALING PATHWAYS TO THERAPEUTIC TOOLS
影响因子：
--
作者：
Hiscott, J;Grandvaux, N;Lin, RT
通讯作者：
Lin, RT
影响因子：
--
作者：
McDermott, Jason E.;Costa, Michelle;Tilton, Susan C.
通讯作者：
Tilton, Susan C.