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

Graeme Lancaster, Katherine Langley, Nils Anton Berglund, Helene Kammoun, Saskia Reibe, Emma Estevez, Jacquelyn Weir, Natalie Mellett, Gerard Pernes, James Conway, Man Lee, Paul Timpson, Andrew Murphy, Seth Masters, Steve Gerondakis, Nenad Bartonicek, Dominik Kaczorowski, Marcel Dinger, Peter Meikle, Peter Bond and Mark Febbraio

Cell Metabolism 2018.


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 long-chain 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.

Our Thoughts on This Paper

Free fatty acids are able to promote inflammation in macrophages and other cells, a signaling mechanism that is key to understanding the relationships between obesity, lipid flux, inflammation and insulin resistance. One model posited that saturated fatty acids can directly activate TLR4 receptors, data that was supported by resistance to palmitate-induced JNK activation in Tlr4 knockouts.

Lancaster et al. and the Mark Febbraio lab present several studies arguing against that simple model, and instead provide very compelling data that supports the hypothesis that palmitate does not signal directly, but instead suggests that non-FFA TLR4 activation primes cells to respond to fatty acids through an alternate mechanism.They show that this TLR4-dependent priming effect on JNK is rapamycin sensitive, and is associated with changes in ER stress, and reduced induction of several bioactive lipids. Understanding the precise mechanisms and consequences of inflammation-induced reprogramming, and the extent to which this occurs in other cell types will be fascinating to follow.

These comments are cross-posted at Faculty of 1000 Prime.

Written by Dave Bridges on April 28, 2018.


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