Abstract
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. Saturated fatty acids are believed to be TLR4 agonists, promoting macrophage activation and obesity-associated inflammation. Lancaster et al. demonstrate that the inflammatory fatty acid palmitate is actually not a TLR4 agonist. TLR4 is, however, required for palmitate-induced inflammation through TLR4-dependent priming and altered cellular metabolism, thus reconciling discordant observations.
| Original language | English |
|---|---|
| Pages (from-to) | 1096-1110 |
| Number of pages | 16 |
| Journal | Cell Metabolism |
| Volume | 27 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 1 May 2018 |
Keywords
- inflammation
- innate immunity
- metabolism
- obesity
- toll-like receptors
Cite this
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Evidence that TLR4 Is Not a Receptor for Saturated Fatty Acids but Mediates Lipid-Induced Inflammation by Reprogramming Macrophage Metabolism. / Lancaster, Graeme I.; Langley, Katherine G.; Berglund, Nils Anton; Kammoun, Helene L.; Reibe, Saskia; Estevez, Emma; Weir, Jacquelyn; Mellett, Natalie A.; Pernes, Gerard; Conway, James R.W.; Lee, Man K.S.; Timpson, Paul; Murphy, Andrew J. ; Masters, Seth L.; Gerondakis, Steve ; Bartonicek, Nenad; Kaczorowski, Dominik C.; Dinger, Marcel E; Meikle, Peter J.; Bond, Peter J.; Febbraio, Mark A.
In: Cell Metabolism, Vol. 27, No. 5, 01.05.2018, p. 1096-1110.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Evidence that TLR4 Is Not a Receptor for Saturated Fatty Acids but Mediates Lipid-Induced Inflammation by Reprogramming Macrophage Metabolism
AU - Lancaster, Graeme I.
AU - Langley, Katherine G.
AU - Berglund, Nils Anton
AU - Kammoun, Helene L.
AU - Reibe, Saskia
AU - Estevez, Emma
AU - Weir, Jacquelyn
AU - Mellett, Natalie A.
AU - Pernes, Gerard
AU - Conway, James R.W.
AU - Lee, Man K.S.
AU - Timpson, Paul
AU - Murphy, Andrew J.
AU - Masters, Seth L.
AU - Gerondakis, Steve
AU - Bartonicek, Nenad
AU - Kaczorowski, Dominik C.
AU - Dinger, Marcel E
AU - Meikle, Peter J.
AU - Bond, Peter J.
AU - Febbraio, Mark A.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - 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. Saturated fatty acids are believed to be TLR4 agonists, promoting macrophage activation and obesity-associated inflammation. Lancaster et al. demonstrate that the inflammatory fatty acid palmitate is actually not a TLR4 agonist. TLR4 is, however, required for palmitate-induced inflammation through TLR4-dependent priming and altered cellular metabolism, thus reconciling discordant observations.
AB - 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. Saturated fatty acids are believed to be TLR4 agonists, promoting macrophage activation and obesity-associated inflammation. Lancaster et al. demonstrate that the inflammatory fatty acid palmitate is actually not a TLR4 agonist. TLR4 is, however, required for palmitate-induced inflammation through TLR4-dependent priming and altered cellular metabolism, thus reconciling discordant observations.
KW - inflammation
KW - innate immunity
KW - metabolism
KW - obesity
KW - toll-like receptors
UR - http://www.scopus.com/inward/record.url?scp=85045464431&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2018.03.014
DO - 10.1016/j.cmet.2018.03.014
M3 - Article
VL - 27
SP - 1096
EP - 1110
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 5
ER -