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

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2017 Jan 3

PMID 28041958

Citations 171

Authors

Yumiko Oishi

Nathanael J Spann

Verena M Link

Evan D Muse

Tobias Strid

Chantle Edillor

Matthew J Kolar

Takashi Matsuzaka

Sumio Hayakawa

Jenhan Tao

Minna U Kaikkonen

Aaron F Carlin

Michael T Lam

Ichiro Manabe

Hitoshi Shimano

Alan Saghatelian

Christopher K Glass

Affiliations

Soon will be listed here.

Abstract

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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References

Ostuni R, Piccolo V, Barozzi I, Polletti S, Termanini A, Bonifacio S . Latent enhancers activated by stimulation in differentiated cells. Cell. 2013; 152(1-2):157-71. DOI: 10.1016/j.cell.2012.12.018. View

Calkin A, Tontonoz P . Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol. 2012; 13(4):213-24. PMC: 3597092. DOI: 10.1038/nrm3312. View

REPA J, Turley S, Lobaccaro J, Medina J, Li L, Lustig K . Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science. 2000; 289(5484):1524-9. DOI: 10.1126/science.289.5484.1524. View

Rodriguez-Prados J, Traves P, Cuenca J, Rico D, Aragones J, Martin-Sanz P . Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J Immunol. 2010; 185(1):605-14. DOI: 10.4049/jimmunol.0901698. View

Huang S, Everts B, Ivanova Y, OSullivan D, Nascimento M, Smith A . Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol. 2014; 15(9):846-55. PMC: 4139419. DOI: 10.1038/ni.2956. View

Kaikkonen M, Spann N, Heinz S, Romanoski C, Allison K, Stender J . Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol Cell. 2013; 51(3):310-25. PMC: 3779836. DOI: 10.1016/j.molcel.2013.07.010. View

Iyer S, Ghaffari A, Cheng G . Lipopolysaccharide-mediated IL-10 transcriptional regulation requires sequential induction of type I IFNs and IL-27 in macrophages. J Immunol. 2010; 185(11):6599-607. PMC: 4103176. DOI: 10.4049/jimmunol.1002041. View

Castrillo A, Joseph S, Vaidya S, Haberland M, Fogelman A, Cheng G . Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. Mol Cell. 2003; 12(4):805-16. DOI: 10.1016/s1097-2765(03)00384-8. View

A-Gonzalez N, Bensinger S, Hong C, Beceiro S, Bradley M, Zelcer N . Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity. 2009; 31(2):245-58. PMC: 2791787. DOI: 10.1016/j.immuni.2009.06.018. View

10.

Raetz C, Garrett T, Reynolds C, Shaw W, Moore J, Smith Jr D . Kdo2-Lipid A of Escherichia coli, a defined endotoxin that activates macrophages via TLR-4. J Lipid Res. 2006; 47(5):1097-111. DOI: 10.1194/jlr.M600027-JLR200. View

11.

Goldstein J, DeBose-Boyd R, Brown M . Protein sensors for membrane sterols. Cell. 2006; 124(1):35-46. DOI: 10.1016/j.cell.2005.12.022. View

12.

Shimano H, Shimomura I, Hammer R, Herz J, Goldstein J, Brown M . Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene. J Clin Invest. 1997; 100(8):2115-24. PMC: 508404. DOI: 10.1172/JCI119746. View

13.

Creyghton M, Cheng A, Welstead G, Kooistra T, Carey B, Steine E . Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010; 107(50):21931-6. PMC: 3003124. DOI: 10.1073/pnas.1016071107. View

14.

Xu H, Barnes G, Yang Q, Tan G, Yang D, Chou C . Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003; 112(12):1821-30. PMC: 296998. DOI: 10.1172/JCI19451. View

15.

REPA J, Liang G, Ou J, Bashmakov Y, Lobaccaro J, Shimomura I . Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev. 2000; 14(22):2819-30. PMC: 317055. DOI: 10.1101/gad.844900. View

16.

Heinz S, Benner C, Spann N, Bertolino E, Lin Y, Laslo P . Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 2010; 38(4):576-89. PMC: 2898526. DOI: 10.1016/j.molcel.2010.05.004. View

17.

Mantovani A, Biswas S, Galdiero M, Sica A, Locati M . Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol. 2012; 229(2):176-85. DOI: 10.1002/path.4133. View

18.

Wynn T, Chawla A, Pollard J . Macrophage biology in development, homeostasis and disease. Nature. 2013; 496(7446):445-55. PMC: 3725458. DOI: 10.1038/nature12034. View

19.

Li P, Spann N, Kaikkonen M, Lu M, Oh D, Fox J . NCoR repression of LXRs restricts macrophage biosynthesis of insulin-sensitizing omega 3 fatty acids. Cell. 2013; 155(1):200-214. PMC: 4131699. DOI: 10.1016/j.cell.2013.08.054. View

20.

Dennis E, Deems R, Harkewicz R, Quehenberger O, Brown H, Milne S . A mouse macrophage lipidome. J Biol Chem. 2010; 285(51):39976-85. PMC: 3000979. DOI: 10.1074/jbc.M110.182915. View