FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages

WQ Fan, H Morinaga, JJ Kim, E Bae, NJ Spann… - The EMBO …, 2010 - embopress.org
WQ Fan, H Morinaga, JJ Kim, E Bae, NJ Spann, S Heinz, CK Glass, JM Olefsky
The EMBO journal, 2010embopress.org
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 …
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.
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