FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages
FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages
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DOI：
10.1038/emboj.2010.268
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发表时间：
2010-12-15
期刊：
影响因子：
11.4
通讯作者：
Olefsky, Jerrold M.
中科院分区：
文献类型：
--
作者：
Fan, WuQiang;Morinaga, Hidetaka;Olefsky, Jerrold M.
巨噬细胞介导的炎症反应是肥胖相关组织炎症和胰岛素抵抗的关键病因学组成部分。转录因子FoxO 1是细胞代谢、细胞周期和细胞死亡的关键调节因子。其活性受到磷酸肌醇-3-激酶-AKT（PI 3 K-Akt）通路的严格调节，该通路导致FoxO 1的磷酸化、细胞质滞留和失活。在这里，我们发现FoxO 1通过增强成熟巨噬细胞中Tlr 4介导的信号传导来促进炎症。通过染色质免疫沉淀（ChIP）结合大规模平行测序（ChIP-Seq），我们发现FoxO 1结合到Tlr 4基因本身内的多个增强子样元件，以及许多Tlr 4信号通路基因中的位点。虽然FoxO 1增强Tlr 4信号传导，但后者的激活诱导AKT并随后使FoxO 1失活，从而建立自限性炎症机制。鉴于巨噬细胞Tlr 4在转导外源性促炎信号中的中心作用，FoxO 1在巨噬细胞中作为Tlr 4基因及其炎症通路的转录调节因子的新功能突出了FoxO 1作为整合肥胖和胰岛素抵抗背景下炎症反应的关键分子适配器。The EMBO Journal（2010）29，4223-4236. doi：10.1038/doj.2010.268; 2010年11月2日在线发布
The macrophage-mediated inflammatory response is a key etiologic component of obesity-related tissue inflammation and insulin resistance. The transcriptional factor FoxO1 is a key regulator of cell metabolism, cell cycle and cell death. Its activity is tightly regulated by the phosphoinositide- 3-kinase-AKT (PI3K-Akt) pathway, which leads to phosphorylation, cytoplasmic retention and inactivation of FoxO1. Here, we show that FoxO1 promotes inflammation by enhancing Tlr4-mediated signalling in mature macrophages. By means of chromatin immunoprecipitation (ChIP) combined with massively parallel sequencing (ChIP-Seq), we show that FoxO1 binds to multiple enhancer- like elements within the Tlr4 gene itself, as well as to sites in a number of Tlr4 signalling pathway genes. While FoxO1 potentiates Tlr4 signalling, activation of the latter induces AKT and subsequently inactivates FoxO1, establishing a self-limiting mechanism of inflammation. Given the central role of macrophage Tlr4 in transducing extrinsic proinflammatory signals, the novel functions for FoxO1 in macrophages as a transcriptional regulator of the Tlr4 gene and its inflammatory pathway, highlights FoxO1 as a key molecular adaptor integrating inflammatory responses in the context of obesity and insulin resistance. The EMBO Journal (2010) 29, 4223-4236. doi: 10.1038/emboj.2010.268; Published online 2 November 2010