Fatty acids as metabolic mediators in innate immunity

Kopp, Andrea; Groß, Philipp; Falk, Werner; Bala, Margarita; Weigert, Johanna; Buechler, Christa; Neumeier, Markus; Schölmerich, Jürgen; Schäffler, Andréas

doi:10.1111/j.1365-2362.2009.02185.x

Cited by 43 publications

(36 citation statements)

References 21 publications

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“…12 14 15 However, the exact nature of this interaction is still not quite clear: On the one hand, there is no direct binding of radiolabelled saturated FFA to TLR4 (more specifically, a soluble fusion complex consisting of the FLAG-tagged extracellular part of TLR-4 fused to full-length MD-2 via a flexible linker); 12 on the other hand, the polyunsaturated fatty acid eicosapentaenoic acid blocks LPS binding to an experimental LPS trap. 15 Whether FFA mediate TLR4 activation by inducing its dimerisation is discussed controversially. Lee et al 33 found no effect on TLR4 dimerisation, while Wong et al 34 found that saturated fatty acid induced TLR4 dimerisation.…”

Section: Discussionmentioning

confidence: 99%

“…Serum FFA levels are increased in obese individuals compared with lean individuals, 5 and chronically elevated FFA levels in vivo have been shown to cause various detrimental effects, including impaired insulin sensitivity of muscles 6 and liver, 7 8 endothelial dysfunction, 9 hypertension 10 and increased very low-density lipoprotein production. 11 In addition, FFA affect gene expression of adipocytes, 12 macrophages 13 14 and monocytes 15 in vitro.…”

Section: Introductionmentioning

confidence: 99%

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Free fatty acids: potential proinflammatory mediators in rheumatic diseases

et al. 2013

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Objectives Due to their role in inflammatory metabolic diseases, we hypothesised that free fatty acids (FFA) are also involved in inflammatory joint diseases. To test this hypothesis, we analysed the effect of FFA on synovial fibroblasts (SF), human chondrocytes and endothelial cells. We also investigated whether the toll-like receptor 4 (TLR4), which can contribute to driving arthritis, is involved in FFA signalling. Methods Rheumatoid arthritis SF, osteoarthritis SF, psoriatic arthritis SF, human chondrocytes and endothelial cells were stimulated in vitro with different FFA. Immunoassays were used to quantify FFA-induced protein secretion. TLR4 signalling was inhibited extracellularly and intracellularly. Fatty acid translocase (CD36), responsible for transporting long-chain FFA into the cell, was also inhibited. Results In rheumatoid arthritis synovial fibroblasts (RASF), FFA dose-dependently enhanced the secretion of the proinflammatory cytokine IL-6, the chemokines IL-8 and MCP-1, as well as the matrix-degrading enzymes pro-MMP1 and MMP3. The intensity of the response was mainly dependent on the patient rather than on the type of disease. Both saturated and unsaturated FFA showed similar effects on RASF, while responses to the different FFA varied for human chondrocytes and endothelial cells. Extracellular and intracellular TLR4 inhibition as well as fatty acid transport inhibition blocked the palmitic acid-induced IL-6 secretion of RASF. Conclusions The data show that FFA are not only metabolic substrates but may also directly contribute to articular inflammation and degradation in inflammatory joint diseases. Moreover, the data suggest that, in RASF, FFA exert their effects via TLR4 and require extracellular and intracellular access to the TLR4 receptor complex.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Free fatty acids: potential proinflammatory mediators in rheumatic diseases

et al. 2013

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“…S9). Although we and others previously reported some related facts underlying this conclusion, which were observed in a number of different physiological and experimental conditions (12,14,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33), we would like to emphasize that this study, which focused on AIM, has uniquely linked apparently independent elements to a process that occurs during the progression to obesity.…”

Section: Resultsmentioning

confidence: 95%

“…Thus, it is plausible that an increase in blood AIM may induce vigorous lipolysis in obese adipose tissues, and saturated fatty acids effluxed from adipocytes as a result of lipolysis might activate chemokine production in adipocytes via the stimulation of TLR(s) in a paracrine/autocrine fashion (26)(27)(28). Indeed, palmitic and stearic acids, the major fatty acids comprising triglyceride droplets (29) and well known as stimulators of TLR4 and TLR2 (21,25,30,31), were identified as the components released by adipocytes in response to lipolysis induced by AIM or C75 when the profile of fatty acids in AIM CM and C75 CM was evaluated by gas-chromatography massspectrometry analysis. Consistent with this result, both AIM CM and C75 CM efficiently stimulated the TLR signaling cascade and chemokine production in 3T3-L1 adipocytes, as assessed by degradation of IkBα (Fig.…”

Section: Fatty Acids Effluxed From Adipocytes In Response To Aim-depementioning

confidence: 99%

Apoptosis inhibitor of macrophage (AIM) is required for obesity-associated recruitment of inflammatory macrophages into adipose tissue

Kurokawa

Nagano

Ohara

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Infiltration of inflammatory macrophages into adipose tissues with the progression of obesity triggers insulin resistance and obesity-related metabolic diseases. We recently reported that macrophage-derived apoptosis inhibitor of macrophage (AIM) protein is increased in blood in line with obesity progression and is incorporated into adipocytes, thereby inducing lipolysis in adipose tissue. Here we show that such a response is required for the recruitment of adipose tissue macrophages. In vitro, AIM-dependent lipolysis induced an efflux of palmitic and stearic acids from 3T3-L1 adipocytes, thereby stimulating chemokine production in adipocytes via activation of toll-like receptor 4 (TLR4). In vivo administration of recombinant AIM to TLR4 -deficient ( TLR4 −/− ) mice resulted in induction of lipolysis without chemokine production in adipose tissues. Consistently, mRNA levels for the chemokines that affect macrophages were far lower in AIM -deficient ( AIM −/− ) than in wild-type ( AIM +/+ ) obese adipose tissue. This reduction in chemokine production resulted in a marked prevention of inflammatory macrophage infiltration into adipose tissue in obese AIM −/− mice, although these mice showed more advanced obesity than AIM +/+ mice on a high-fat diet. Diminished macrophage infiltration resulted in decreased inflammation locally and systemically in obese AIM −/− mice, thereby protecting them from insulin resistance and glucose intolerance. These results indicate that the increase in blood AIM is a critical event for the initiation of macrophage recruitment into adipose tissue, which is followed by insulin resistance. Thus, AIM suppression might be therapeutically applicable for the prevention of obesity-related metabolic disorders.

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“…A diferencia de la inflamación aguda o clásica inducida por PAMP, la respuesta asociada con diferentes molécu-las derivadas de un estado metabólico alterado o «DAMP metabólicos» conduce a una inflamación de menor intensidad, mayor duración y sistémica 14 . De esta forma, distintos metabolitos han sido vinculados como generadores de inflamación sistémica de grado bajo a través de su unión a TLR 14 .…”

Section: El Inicio De La Inflamación Sistémica De Grado Bajo Depende unclassified