FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages.
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.
Division of Endocrinology-Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0673, USA.
Wuqiang
W
Fan
Hidetaka
H
Morinaga
Jane J
JJ
Kim
Eunju
E
Bae
Nathanael J
NJ
Spann
Sven
S
Heinz
Christopher K
CK
Glass
Jerrold M
JM
Olefsky
D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D011485:Protein Binding; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis*
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D018836:Inflammation Mediators; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D004247:DNA