| First Author | Fan W | Year | 2010 |
| Journal | EMBO J | Volume | 29 |
| Issue | 24 | Pages | 4223-36 |
| PubMed ID | 21045807 | Mgi Jnum | J:167177 |
| Mgi Id | MGI:4867370 | Doi | 10.1038/emboj.2010.268 |
| Citation | Fan W, et al. (2010) FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages. EMBO J 29(24):4223-36 |
| abstractText | 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. |
