Evidence that TLR4 Is Not a Receptor for Saturated Fatty Acids but Mediates Lipid-Induced Inflammation by Reprogramming Macrophage Metabolism

Evidence that TLR4 Is Not a Receptor for Saturated Fatty Acids but Mediates Lipid-Induced Inflammation by Reprogramming Macrophage Metabolism

Cell Metabolism

10.1016/j.cmet.2018.03.014

https://doi.org/10.1016/j.cmet.2018.03.014

Graeme I. Lancaster, Katherine G. Langley, Nils Anton Berglund, Helene L. Kammoun, Saskia Reibe, Emma Estevez, Jacquelyn Weir, Natalie A. Mellett, Gerard Pernes, James R.W. Conway, Man K.S. Lee, Paul Timpson, Andrew J. Murphy, Seth L. Masters, Steve Gerondakis, Nenad Bartonicek, Dominik C. Kaczorowski, Marcel E. Dinger, Peter J. Meikle, Peter J. Bond, Mark A. Febbraio

19 April 2018

Graeme I. Lancaster, Katherine G. Langley, Nils Anton Berglund, Helene L. Kammoun, Saskia Reibe, Emma Estevez, Jacquelyn Weir, Natalie A. Mellett, Gerard Pernes, James R.W. Conway, Man K.S. Lee, Paul Timpson, Andrew J. Murphy, Seth L. Masters, Steve Gerondakis, Nenad Bartonicek, Dominik C. Kaczorowski, Marcel E. Dinger, Peter J. Meikle, Peter J. Bond, Mark A. Febbraio, Evidence that TLR4 Is Not a Receptor for Saturated Fatty Acids but Mediates Lipid-Induced Inflammation by Reprogramming Macrophage Metabolism, Cell Metabolism, Volume 27, Issue 5, 2018, Pages 1096-1110.e5, ISSN 1550-4131, https://doi.org/10.1016/j.cmet.2018.03.014.

Chronic inflammation is a hallmark of obesity and is linked to the development of numerous diseases. The activation of toll-like receptor 4 (TLR4) by longchain saturated fatty acids (lcSFAs) is an important process in understanding how obesity initiates inflammation. While experimental evidence supports an important role for TLR4 in obesity-induced inflammation in vivo, via a mechanism thought to involve direct binding to and activation of TLR4 by lcSFAs, several lines of evidence argue against lcSFAs being direct TLR4 agonists. Using multiple orthogonal approaches, we herein provide evidence that while loss-of-function models confirm that TLR4 does, indeed, regulate lcSFA-induced inflammation, TLR4 is not a receptor for lcSFAs. Rather, we show that TLR4-dependent priming alters cellular metabolism, gene expression, lipid metabolic pathways, and membrane lipid composition, changes that are necessary for lcSFA-induced inflammation. These results reconcile previous discordant observations and challenge the prevailing view of TLR4’s role in initiating obesity-induced inflammation.

PublisherCopyrights

This study was funded, in part, by the National Health and Medical Research Council (NHMRC project grant no. 586636 to M.A.F. and G.I.L.) and the Victorian Governments Operational Support Program. M.A.F. is a Senior Principal Research Fellow of the NHMRC (APP1116936). S.L.M. acknowledges funding from the Sylvia and Charles Viertel Foundation, HHMI-Wellcome International Research Scholarship, and Glaxosmithkline.

https://oar.a-star.edu.sg/communities-collections/articles/14186

1550-4131
1932-7420

Bioinformatics Institute