SREBP1 Contributes to Resolution of Pro-inflammatory TLR4 Signaling by Reprogramming Fatty Acid Metabolism

Macrophages play pivotal roles in both the induction and resolution phases of inflammatory processes. Macrophages have been shown to synthesize anti-inflammatory fatty acids in an LXR-dependent manner, but whether the production of these species contributes to the resolution phase of inflammatory re...

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Published in:Cell metabolism Vol. 25; no. 2; p. 412
Main Authors: Oishi, Yumiko, Spann, Nathanael J, Link, Verena M, Muse, Evan D, Strid, Tobias, Edillor, Chantle, Kolar, Matthew J, Matsuzaka, Takashi, Hayakawa, Sumio, Tao, Jenhan, Kaikkonen, Minna U, Carlin, Aaron F, Lam, Michael T, Manabe, Ichiro, Shimano, Hitoshi, Saghatelian, Alan, Glass, Christopher K
Format: Journal Article
Language:English
Published: United States 07.02.2017
Subjects:
Animals
Base Sequence
Biosynthetic Pathways - drug effects
Biosynthetic Pathways - genetics
Enhancer Elements, Genetic - genetics
Fatty Acids - metabolism
Inflammation - genetics
Inflammation - pathology
Lipid Metabolism - drug effects
Lipopolysaccharides - pharmacology
Liver X Receptors - metabolism
Macrophages - drug effects
Macrophages - metabolism
Male
Mice, Inbred C57BL
Phenotype
Signal Transduction - drug effects
Sterol Regulatory Element Binding Protein 1 - metabolism
Time Factors
Toll-Like Receptor 4 - metabolism
innate immunity
unsaturated fatty acids
inflammation
fatty acid metabolism
transcriptional regulation
EPA
lipid metabolism
SREBP1
DHA
resolution
ISSN:1932-7420, 1932-7420
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Summary:Macrophages play pivotal roles in both the induction and resolution phases of inflammatory processes. Macrophages have been shown to synthesize anti-inflammatory fatty acids in an LXR-dependent manner, but whether the production of these species contributes to the resolution phase of inflammatory responses has not been established. Here, we identify a biphasic program of gene expression that drives production of anti-inflammatory fatty acids 12-24 hr following TLR4 activation and contributes to downregulation of mRNAs encoding pro-inflammatory mediators. Unexpectedly, rather than requiring LXRs, this late program of anti-inflammatory fatty acid biosynthesis is dependent on SREBP1 and results in the uncoupling of NFκB binding from gene activation. In contrast to previously identified roles of SREBP1 in promoting production of IL1β during the induction phase of inflammation, these studies provide evidence that SREBP1 also contributes to the resolution phase of TLR4-induced gene activation by reprogramming macrophage lipid metabolism.
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ISSN:1932-7420
1932-7420
DOI:10.1016/j.cmet.2016.11.009