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FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages.

ABSTRACT: 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.

SUBMITTER: Fan W

PROVIDER: S-EPMC3018786 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages.

Fan Wuqiang W Morinaga Hidetaka H Kim Jane J JJ Bae Eunju E Spann Nathanael J NJ Heinz Sven S Glass Christopher K CK Olefsky Jerrold M JM

The EMBO journal 20101102 24

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 mat ...[more]

PMID: 21045807

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FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages.

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FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages.

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