Cell Biology/Signaling:
Saturated Fatty Acids Do Not Directly Stimulate Toll-Like Receptor Signaling
Erridge and Samani (1 November 2009)
[Abstract]
[Full text]
[PDF]
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Saturated Fatty Acids Do Not Directly Stimulate Toll-Like Receptor Signaling
Response to Hwang, et al. |
7 October 2009 |
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Clett Erridge
Glenfield General Hospital,
Nilesh J Samani
Send letter to journal:
Re: Response to Hwang, et al.
ce55{at}leicester.ac.uk Clett Erridge, et al.
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We welcome the comments of Hwang et al, as the hypothesis that
saturated fatty acids (SFAs) may stimulate Toll-like receptor (TLR)-
signalling has become a central component of much current research in the
fields of atherosclerosis and insulin resistance, and accordingly requires
rigorous testing and debate. In particular, several concerns have been
raised regarding the design of our study and our interpretation of the
results of this and previous studies of SFA signalling.
To address these points in turn, Hwang et al first raise the concern
that we may have been inappropriately selective in our choice to examine
the properties of a contaminated BSA in our studies (ie BSA-2), suggesting
that we should have also examined a non-contaminated BSA. However,
extensive experimentation was in fact performed using such a BSA, which we
established to be non-contaminated, and the results of these studies are
presented in Figure 4 of our report [1]. We showed that when SFA-BSA
complexes were made using this non-contaminated BSA, no TLR-dependent
signalling could be detected using diverse readouts. In fact, we went
further than previous studies to show that the SFA/BSA complexes contained
complexed fatty acids at expected molar ratios (Fig 4 A).
Next, Hwang et al suggest that our conclusions are not valid as we
did not include co-transfection of TLR1 or TLR6 in our TLR-transfection
experiments, citing their hypothesis that SFA signalling via TLR2 may
require co-operation with the co-receptors TLR1 or TLR6. However, it
should be noted that the cell line we chose to use for these experiments
(HEK-293) is established to express sufficient levels of endogenous TLR1
and TLR6 [2-10], such that transfection with TLR2 alone endows full
responsiveness of these cells to ligands that require TLR1 and TLR6 co-
operation with TLR2, such as the di-acyl and tri-acyl lipopeptides FSL-1
and Pam3CSK4, respectively [2-10]. There is therefore no need for
additional TLR1 or TLR6 transfection over baseline in these experiments,
as supported by many previous studies using this system [2-10].
Hwang and colleagues also point out that not all studies reporting
SFA-induced TLR-signalling have employed BSA complexing, as some studies
have examined the properties of sodiated SFAs without BSA complexing [11-
14]. We acknowledge that this is correct and to address this possiblity,
we also examined the potential of sodiated SFAs to stimulate TLR-
signalling in the absence of BSA complexing. We found no evidence of TLR-
signalling induced by sodiated SFAs in these experiments, as clearly
presented in Supplementary Figure III of our recent report [1]. The
divergent findings between the present and previous studies of sodiated
SFAs may perhaps be explained by variations in the extent of LPS or
lipopeptide contamination between batches of commercially sourced
reagents. With this possibility in mind, we note that only Hwang and
colleagues have reported induction of TLR-signalling by sodiated SFAs [11-
14], while the other studies reviewed in our article examined SFAs
complexed to BSA.
Next, Hwang et al suggest that we may have prematurely discounted SFA
-induced TLR-signalling as appropriate controls for potential bacterial
contaminants were performed in previous studies showing the induction of
TLR-dependent mediators by SFA/BSA complexes. Specifically, Hwang et al
point out that polymyxin-B was used to neutralise LPS contamination in 3
of the 13 studies reviewed in our report [14-16], and limulus assays
indicated that levels of LPS contamination were too low to affect the
results in 3 other studies [17-19]. However, as discussed in our report,
we found that neither of these strategies are effective at detecting or
neutralising lipopeptide or flagellin contaminants, which we and others
have shown may be common contaminants of laboratory reagents, such as BSA
(supplementary figures IV and X and [20]).
Thus, although Hwang et al are correct that some of the previous
studies of SFA signalling may have employed commercially-sourced 'low
endotoxin' BSA to prepare SFA/BSA complexes [21], lipopeptide or other
contaminants could nevertheless be present in such reagents that may
explain their pro-inflammatory signatures. Another point that should be
borne in mind is that the limulus assay is readily confounded by LPS-
binding proteins, such as albumin, which are established to lead to marked
underestimation of endotoxin concentrations in preparations containing
such proteins. Indeed, as little as 1 μg/ml LBP or BPI was shown to
completely block the ability of the limulus assay to detect LPS, and
albumin itself was also shown to possess this property [22,23]. The extent
of endotoxin contamination of BSA preparations used in previous studies
may therefore have been significantly underestimated on the occasions
where the limulus assay was used for LPS quantification.
A further possibility suggested by Hwang et al is that we may have
observed TLR-dependent signalling of SFAs if we had used low serum
conditions in our experiments. In fact, consistent with our earlier
studies [24-26], and the methods detailed in the supplement, cells were
routinely challenged with reagents in medium supplemented with 1% serum,
as we have found this to provide the optimum level of fold-induction in
our previous studies [24-26]. Thus, differences in serum concentrations
are unlikely to explain the divergent findings of the present and previous
studies.
Finally, with respect to the previous in vivo studies of modulation
of TLR-signalling in response to diets rich in saturated fat, we would
suggest that although these studies do indicate a role for TLRs in
diseases such as atherosclerosis and insulin resistance, it does not
necessarily follow that SFAs must be the causative agents of TLR-
stimulation in these studies. With this notion in mind, it may be helpful
to consider the implications of the SFA/TLR hypothesis in a physiological
context, as several previous studies of SFA signalling have reported
maximal activation of TLR4 signalling at concentrations of 75 to 100
μM in vitro [11-13,21,27]. Moreover, Hwang et al showed that 75
μM SFA stimulated TLR4 signalling in cultured cells at a level
comparable with 200 ng/ml LPS [12], a concentration that would result in
symptoms of severe endotoxaemia in human subjects [28]. If SFAs truly did
stimulate TLR-signalling in the manner proposed in previous reports, these
results suggest that subjects should experience symptoms concordant with
severe endotoxaemia (ie systemic TLR4 activation), including fever, shock
and multiple organ failure, if circulating SFA concentrations reached or
exceeded 75 μM in vivo [28]. Notably, circulating SFA concentrations
routinely exceed 150 μM in healthy subjects [29,30], yet such
symptoms are not generally experienced.
In conclusion, we have performed and reported the results of the
control experiments suggested by Hwang and colleagues, and the results of
these experiments support our original conclusion that SFAs do not
stimulate TLR-signalling. Further work will be required to elucidate
alternative mechanisms that may link dietary fat intake with TLR-dependent
chronic inflammatory pathologies such as atherosclerosis and insulin
resistance.
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Neumeier M, Kopp A, Schoelmerich J, Falk W. Fatty acid-induced induction
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Clett Erridge *, Nilesh J Samani
* Corresponding author
Department of Cardiovascular Sciences
University of Leicester
Clinical Sciences Wing
Glenfield Hospital
Groby Road
Leicester
LE3 9QP
Email: ce55@le.ac.uk
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Saturated Fatty Acids Do Not Directly Stimulate Toll-Like Receptor Signaling
Saturated fatty acid-induced activation of Toll-like receptors (TLRs) is fatty acid-specific effect |
7 October 2009 |
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Daniel H Hwang,
Research Molecular Biologist
USDA/ARS Western Human Nutrition Research Center,
Yoshihiro Ogawa, Andreas Schaeffler
Send letter to journal:
Re: Saturated fatty acid-induced activation of Toll-like receptors (TLRs) is fatty acid-specific effect
daniel.hwang{at}ars.usda.gov Daniel H Hwang, et al.
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Untitled Document
Erridge and Samani (1) reported that the in vitro activation of TLR2 and TLR4 by saturated fatty acids (SFAs) is due to TLR agonists contaminated in BSA preparations. Here, we wish to present our view that there are critical flaws in the experimental design and data interpretation which we believe led to the erroneous conclusion that SFAs do not directly stimulate TLR-dependent signaling. Fig.1 in their report showed that SFAs alone do not activate NFκB in 293 cells transfected with TLR2, TLR4 or TLR5 expression plasmids. However, SFAs conjugated with the fatty acid-free BSA (BSA-2) activated NFκB in the cells transfected with TLR2 or TLR4/MD2 (panels appear to be wrongly labeled in the legend). Thus, they concluded that NFκB activation by the SFA-BSA preparations reported by many investigators is attributable to other TLR agonists contaminated in BSA preparations instead of the fatty acid-specific effect. This conclusion is invalid because they have not included proper controls in their experiments. First, SFAs do not activate TLR2 alone, but they activate TLR2 and TLR6 (or TLR1) heterodimer (2). SFAs also do not activate TLR5 (2). Therefore, 293 cells transfected with TLR2 alone or TLR5 are not appropriate models to demonstrate the stimulatory effects of SFAs on TLR activation. Second, they examined five different BSA preparations for TLR activation and found that two of them activated TLRs, while the other three preparations including low endotoxin and fatty acid free BSA preparation (BSA-5, Sigma A8806) did not activate TLR4. They deliberately chose the preparation (BSA-2) that alone can activate TLRs to conjugate SFAs for their studies, and drew the conclusion that all previously reported studies have used the same BSA preparation. Furthermore, they incorrectly stated (1st paragraph in the Results section) that in studies by other investigators (ref.# 18-22 in their report) the same fatty acid free BSA preparation was used to conjugate fatty acids. It should be noted that in the first report demonstrating that SFAs activate TLR4, the low endotoxin and fatty acid free BSA (Sigma A8806) was used to conjugate fatty acids as indicated in "Reagents" section (ref.# 3 in this Letter or ref.# 21 in their report). This BSA preparation (10 uM) alone did not induce the expression of TLR4 target gene products in RAW264.7 cells (3). Therefore, Erridge and Samani (1) should have included SFA-BSA-5 or 3 that alone does not activate TLRs as a proper control. In other studies (ref.#18-20, 22 in their report), sodium salts of fatty acids without BSA were used: thus, contamination of TLR agonists in BSA was not an issue.
The activation of TLR4 by saturated fatty acids has been demonstrated not only through biochemical approaches using 293 cells transfected with TLR plasmids (2-4,6), macrophages (2-6,7), bone marrow-derived dendritic cells (4,7), 3T3L1 cells (8), muscle cells (9), endothelial cells (10), and murine pro-B cell line (5), but also with genetic and dietary approaches using TLR4 or TLR2+4 knockout (6,7) or TLR4 mutant mice (8,11,12). In most of these reports, the issue of TLR agonist contamination in BSA were appropriately addressed by including proper vehicle controls containing BSA alone in the assays, or by measuring the levels of LPS in BSA preparations. Stimulatory effects of saturated fatty acids on TLR4 activation were not attenuated by Polymyxin B indicating no significant contamination of LPS in the SFA-BSA preparation used in these studies (8). Shi et al (6) and Nguyen et al (7) detected 0.03 and 0.04ng/ml of endotoxin in their fatty acid-BSA preparations, respectively. These amounts of endotoxin did not cause the activation of inflammatory signals in the cell types used. In addition, docosahexaenoic acid-BSA inhibited the expression of TLR4 target gene products induced by saturated fatty acid-BSA in these studies (3,6). Kopp et al. (13) found no significant amount of LPS in their BSA preparation as determined by a novel technique using TLR4/MD2 fusion protein as a LPS-trap. Lauric acid and eicosapentaenoic acid conjugated with this BSA preparation reciprocally modulated the expression of TLR4 target gene product COX-2 in RAW264.7 cells, or TNFα in THP-1 cells (3,13). Together, these results indicate that the stimulatory effects of saturated fatty acids and inhibitory effects of n-3 polyunsaturated fatty acids on TLR activation are fatty acid-specific effects rather than the effects of contaminants in BSA.
Therefore, what can be said with the results of Erridge and Samani (1) is that the particular BSA preparation (BSA-2, Sigma A0281) contains contaminants that can activate TLR2 and TLR4. Their results do not disprove that SFAs activate TLR4 or TLR2 dimerized with TLR6 or TLR1. In addition, Fig. 1B in Erridge and Samani (1) showed that SFAs (without BSA) do not activate NFκB in 293 cells transfected with TLR4/MD2. These results contradict those reported by other investigators demonstrating that sodium salt of lauric acid (without BSA conjugation) activates TLR4 and TLR2+4 dimer (2,4,5). Since the SFA was used without BSA conjugation, contamination of TLR agonists in BSA is a non-issue in these studies (2,4,5). Polymyxin B did not attenuate the stimulatory effect of lauric acid on NFκB activation and the expression of COX-2 (TLR4 target gene product) indicating that SFA effects are not due to possible contamination of LPS in the SFA preparation (4, and Fig. 1). Since lauric acid preparation does not activate TLR2 alone (2), the presence of TLR2 agonist contaminants in lauric acid preparation is also unlikely. Thus, stimulatory effects of saturated fatty acids and inhibitory effects of PUFAs are likely to be fatty acid-specific effects. In many studies (2-5, 8,9,11,12) demonstrating that SFAs activate TLRs, cells were treated with fatty acids in low serum media. The stimulatory effects of SFAs on TLR activation (NFκB activation and COX-2 expression) are more pronounced if cells are serum-starved (in medium containing 0.25% FBS) prior to the treatment with fatty acids in the same serum-poor medium as compared to the treatment of cells in the medium containing 10% FBS (Fig. 2). The same condition with serum poor medium has been used in the studies for ref. 2-5. It is not clear why SFA effects are potentiated in the low serum medium.
One possibility is that serum contains many types of lipids that can release free fatty acids including polyunsaturated fatty acids which inhibit TLR activation induced by SFA. Another possibility is that albumin in the serum binds SFA added into the medium making it less available to the cells. In general, effective doses of fatty acid-BSA conjugates are much higher than fatty acid alone (as sodium salt).
Taken all together, the report by Erridge and Samani suggests that caution is needed in selecting and testing BSA preparations for possible contamination of TLR agonists. However, their results neither support their conclusion nor refute the results reported by other investigators that SFAs activate TLR2 dimers and TLR4. The mechanism by which fatty acids modulate the activation of TLRs remains to be elucidated. Schaeffler et al. (14) reported that 14 C-labeled fatty acids do not directly bind TLR4/MD2 complex. However, it is possible that direct binding of fatty acids to TLRs is not required to modulate TLR activation. Wong et al. (5) showed that fatty acids modulate the activation of TLR4 through regulation of dimerization and recruitment of TLR4 into lipid rafts in a reactive oxygen species-dependent manner.
Daniel H. Hwang, Ph.D. (corresponding author)
USDA/ARS Western Human Nutrition Research Center and University of California-Davis, U.S.A. (Daniel.hwang@ars.usda.gov)
Yoshihiro Ogawa, M.D., Ph.D.
Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Japan (ogawa.mmm@mri.tmd.ac.jp)
Andreas Schaeffler, M.D., Ph.D.
Regensburg University Hospital, Department of Internal Medicine I, Germany (andreas.schaeffler@klinik.uni-regensburg.de)
References
1. Erridge C and Samani NJ. Saturated Fatty Acids Do Not Directly Stimulate Toll-Like Receptor Signaling. Arterioscler. Thromb. Vasc. Biol. published online Aug 6, 2009
2. Lee JY, Zhao L, Youn HS, Weatherill AR, Tapping R, Feng L, Lee WH, Fitzgerald KA, Hwang DH. Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1. J Biol Chem. 2004;279:16971?16979
3. Lee JY, Sohn KH, Rhee SH, Hwang D. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem. 2001;276:16683?16689
4. Weatherill AR, Lee JY, Zhao L, Lemay DG, Youn HS, Hwang DH. Saturated and polyunsaturated fatty acids reciprocally modulate dendritic cell functions mediated through TLR4. J Immunol. 2005;174:5390 ?5397
5. Wong SW, Kwon MJ, Choi AMK, Kim HP, Nakahira K, Hwang DH. Fatty acids modulate Toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts. J Biol Chem (August 1, 2009, Epub ahead of print) 2009;284:27384-27392
6. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006;116:3015?3025
7. Nguyen MT, Favelyukis S, Nguyen AK, Reichart D, Scott PA, Jenn A, Liu-Bryan R, Glass CK, Neels JG, Olefsky JM. A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem. 2007;282:35279 ?35292
8. Suganami T, Tanimoto-Koyama K, Nishida J, Itoh M, Yuan X, Mizuarai S, Kotani H, Yamaoka S, Miyake K, Aoe S, Kamei Y, Ogawa Y. Role of the Toll-like receptor 4/NF-kappaB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages. Arterioscler Thromb Vasc Biol. 2007;27:84 ?91.
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12. Suganami T, Yuan X, Shimoda Y, Uchio-Yamada K, Nakagawa N, Shirakawa I, Usami T, Tsukahara T, Nakayama K, Miyamoto Y, Yasuda K, Matsuda J, Kamei Y, Kitajima S, Ogawa Y. Activating transcription factor 3 constitutes a negative feedback mechanism that attenuates saturated fatty acid/toll-like receptor 4 signaling and macrophage activation in obese adipose tissue. Circ Res. 2009;105:25-32
13. Kopp A, Gross P, Falk W, Bala M, Weigert J, Buechler C, Neumeier M, Sch?rich J, Sch䦦ler A. Fatty acids as metabolic mediators in innate immunity. Eur J Clin Invest. 2009 Jun 26. [Epub ahead of print]
14. Schaeffler A, Gross P, Buettner R, Bollheimer C, Buechler C, Neumeier M,
Kopp A, Schoelmerich J, Falk W. Fatty acid-induced induction of Toll-like
receptor-4/nuclear factor-kappaB pathway in adipocytes links nutritional signalling
with innate immunity. Immunology. 2008;126:233?245 |
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