Free fatty acids sensitize dendritic cells to amplify TH1/TH17‐immune responses

Stelzner, Kristin; Herbert, Diana; Popkova, Yulia; Lorz, Axel; Schiller, Jürgen; Gericke, Martin; Klöting, Nora; Blüher, Matthias; Franz, Sandra; Simon, Jan C.; Saalbach, Anja

doi:10.1002/eji.201546263

Cited by 73 publications

(70 citation statements)

References 69 publications

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“…Several studies have indicated the ability of free fatty acids to modulate DC differentiation and responses to LPS [9, 44–46]. However, the direct effect of PA on dendritic cell activation and maturation is unknown.…”

Section: Resultsmentioning

confidence: 99%

“…IL-1β supports the development of Th17 cells [79, 80], and Th17 cells have recently been implicated as a predominant driver of inflammation in human T1D and T2D [81]. In mice, PA primes MoDCs to generate Th1/Th17 responses upon LPS stimulation [44]. This study found no direct effect of PA on human MoDCs, likely due to too short of a treatment time for PA, a weak TLR4 agonist as we have demonstrated here.…”

Section: Discussionmentioning

confidence: 99%

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Palmitic acid is a toll-like receptor 4 ligand that induces human dendritic cell secretion of IL-1β

et al. 2017

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Palmitic acid (PA) and other saturated fatty acids are known to stimulate pro-inflammatory responses in human immune cells via Toll-like receptor 4 (TLR4). However, the molecular mechanism responsible for fatty acid stimulation of TLR4 remains unknown. Here, we demonstrate that PA functions as a ligand for TLR4 on human monocyte derived dendritic cells (MoDCs). Hydrophobicity protein modeling indicated PA can associate with the hydrophobic binding pocket of TLR4 adaptor protein MD-2. Isothermal titration calorimetry quantified heat absorption that occurred during PA titration into TLR4/MD2, indicating that PA binds to TLR4/MD2. Treatment of human MoDCs with PA resulted in endocytosis of TLR4, further supporting the function of PA as a TLR4 agonist. In addition, PA stimulated DC maturation and activation based on the upregulation of DC costimulatory factors CD86 and CD83. Further experiments showed that PA induced TLR4 dependent secretion of the pro-inflammatory cytokine IL-1β. Lastly, our experimental data show that PA stimulation of NF-κB canonical pathway activation is regulated by TLR4 signaling and that reactive oxygen species may be important in upregulating this pro-inflammatory response. Our experiments demonstrate for the first time that PA activation of TLR4 occurs in response to direct molecular interactions between PA and MD-2. In summary, our findings suggest a likely molecular mechanism for PA induction of pro-inflammatory immune responses in human dendritic cells expressing TLR4.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Palmitic acid is a toll-like receptor 4 ligand that induces human dendritic cell secretion of IL-1β

et al. 2017

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“…Although we did not include these adipokines in this study, they could relate to the pathogenesis of the overweight patients with RA. Furthermore, free fatty acid also sensitizes dendritic cells to induce Th17 response, and could be a possible mediator in RA pathogenesis [23]. These points will be addressed in the future.…”

Section: Discussionmentioning

confidence: 99%

Increased serum concentrations of IL-1 beta, IL-21 and Th17 cells in overweight patients with rheumatoid arthritis

et al. 2017

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BackgroundsObesity is associated with worse disease activity and drug responses in patients with rheumatoid arthritis (RA). However, the immunological mechanisms responsible for the relationship between RA and obesity have not yet been clarified in detail. This study aimed to elucidate the immunological mechanisms contributing to the pathogenesis of RA in overweight patients.MethodsThe frequencies of CD4+ T cell, B cell and monocyte subsets were analyzed in RA (n = 81) and healthy donors (n = 99) by flow cytometry, and were compared between three groups (body mass index (BMI) <20, ≥20 to 25, >25). Serum cytokines were measured using multiplex ELISA. Gene expression was analyzed by quantitative PCR. Clinical information was extracted from medical records.ResultsThe frequencies of T helper (Th)17 (CD4+CD45RA-CXCR5-CXCR3-CCR6+) cells and plasmablasts (PB) were significantly increased in patients with RA with BMI >25. Significant correlation was observed between BMI and Th17 cells in patients with RA. No significant differences in cell frequencies between the three BMI groups were observed in the healthy donors. Serum interleukin (IL)-1β and IL-21 significantly correlated with BMI in RA patients. Gene expression patterns in Th17 cells from overweight patients with RA showed the characteristics of pathogenic Th17 cells.ConclusionsQuantitative and qualitative changes in Th17 cells were characteristic in overweight patients with RA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1308-y) contains supplementary material, which is available to authorized users.

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“…Obesity is associated with low-grade chronic inflammation due to deregulation of immune response. Enlarged adipocytes change their secretion pattern into releasing more pro-inflammatory mediators [32]. Accumulating data suggest that reciprocal interactions between the metabolic disturbances and immune system may be a link between the pathogenesis of psoriasis and obesity.…”

Section: Introductionmentioning

confidence: 99%

Serum fatty acid profile in psoriasis and its comorbidity

et al. 2017

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Psoriasis is a chronic inflammatory skin disease that is accompanied by metabolic disturbances and cardio-metabolic disorders. Fatty acids (FAs) might be a link between psoriasis and its comorbidity. The aim of the study was to evaluate serum concentrations of FAs and to investigate their association with the disease activity, markers of inflammation and possible involvement in psoriatic comorbidity: obesity, type 2 diabetes and hypertension. We measured 14 total serum fatty acids content and composition by gas–liquid chromatography and flame-ionization detector after direct in situ transesterification in 85 patients with exacerbated plaque psoriasis and in 32 healthy controls. FAs were grouped according to their biologic properties to saturated FA (SFA), unsaturated FA (UFA), monounsaturated FA (MUFA), n-3 polyunsaturated FA (n-3 PUFA) and n-6 PUFA. Generally, patients characteristic included: Psoriasis Area and Severity Index (PASI), Body Mass Index, inflammatory and biochemical markers, lipid profile and presence of psoriatic comorbidity. We have observed highly abnormal FAs pattern in psoriatic patients both with and without obesity compared to the control group. We have demonstrated association of PASI with low levels of circulating DHA, n-3 PUFA (p = 0.044 and p = 0.048, respectively) and high percent of MUFA (p = 0.024) in the non-obese psoriatic group. The SFA/UFA ratio increased with the duration of the disease (p = 0.03) in all psoriatic patients. These findings indicate abnormal FAs profile in psoriasis which may reflect metabolic disturbances and might play a role in the psoriatic comorbidity.

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Free fatty acids sensitize dendritic cells to amplify TH1/TH17‐immune responses

Cited by 73 publications

References 69 publications

Palmitic acid is a toll-like receptor 4 ligand that induces human dendritic cell secretion of IL-1β

Palmitic acid is a toll-like receptor 4 ligand that induces human dendritic cell secretion of IL-1β

Increased serum concentrations of IL-1 beta, IL-21 and Th17 cells in overweight patients with rheumatoid arthritis

Serum fatty acid profile in psoriasis and its comorbidity

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