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  • Ovid Technologies (Wolters Kluwer Health)  (13)
  • 1
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    Coinhibitory Suppression of T Cell Activation by CD40 Protects Against Obesity and Adipose Tissue Inflammation in Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Circulation Vol. 129, No. 23 ( 2014-06-10), p. 2414-2425
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 129, No. 23 ( 2014-06-10), p. 2414-2425
    Abstract: Costimulatory cascades such as the CD40L-CD40 dyad enhance immune cell activation and inflammation during atherosclerosis. Here, we tested the hypothesis that CD40 directly modulates traits of the metabolic syndrome in diet-induced obesity in mice. Methods and Results— To induce the metabolic syndrome, wild-type or CD40 −/− mice consumed a high-fat diet for 20 weeks. Unexpectedly, CD40 −/− mice exhibited increased weight gain, impaired insulin secretion, augmented accumulation of inflammatory cells in adipose tissue, and enhanced proinflammatory gene expression. This proinflammatory and adverse metabolic phenotype could be transplanted into wild-type mice by reconstitution with CD40-deficient lymphocytes, indicating a major role for CD40 in T or B cells in this context. Conversely, therapeutic activation of CD40 signaling by the stimulating antibody FGK45 abolished further weight gain during the study, lowered glucose levels, improved insulin sensitivity, and suppressed adipose tissue inflammation. Mechanistically, CD40 activation decreased the expression of proinflammatory cytokines in T cells but not in B cells or macrophages. Finally, repopulation of lymphocyte-free Rag1 −/− mice with CD40 −/− T cells provoked dysmetabolism and inflammation, corroborating a protective role of CD40 on T cells in the metabolic syndrome. Finally, levels of soluble CD40 showed a positive association with obesity in humans, suggesting clinical relevance of our findings. Conclusions— We present the surprising finding that CD40 deficiency on T cells aggravates whereas activation of CD40 signaling improves adipose tissue inflammation and its metabolic complications. Therefore, positive modulation of the CD40 pathway might describe a novel therapeutic concept against cardiometabolic disease.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.113.008055
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
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  • 2
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    Inflammatory Pathways Regulated by Tumor Necrosis Receptor–Associated Factor 1 Protect From Metabolic Consequences in Diet-Induced Obesity
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Circulation Research Vol. 122, No. 5 ( 2018-03-02), p. 693-700
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 122, No. 5 ( 2018-03-02), p. 693-700
    Abstract: The coincidence of inflammation and metabolic derangements in obese adipose tissue has sparked the concept of met-inflammation. Previous observations, however, suggest that inflammatory pathways may not ultimately cause dysmetabolism. Objective: We have revisited the relationship between inflammation and metabolism by testing the role of TRAF (tumor necrosis receptor–associated factor)-1, an inhibitory adapter of inflammatory signaling of TNF (tumor necrosis factor)-α, IL (interleukin)-1β, and TLRs (toll-like receptors). Methods and Results: Mice deficient for TRAF-1, which is expressed in obese adipocytes and adipose tissue lymphocytes, caused an expected hyperinflammatory phenotype in adipose tissue with enhanced adipokine and chemokine expression, increased leukocyte accumulation, and potentiated proinflammatory signaling in macrophages and adipocytes in a mouse model of diet-induced obesity. Unexpectedly, TRAF-1 −/− mice were protected from metabolic derangements and adipocyte growth, failed to gain weight, and showed improved insulin resistance—an effect caused by increased lipid breakdown in adipocytes and UCP (uncoupling protein)-1–enabled thermogenesis. TRAF-1–dependent catabolic and proinflammatory cues were synergistically driven by β3-adrenergic and inflammatory signaling and required the presence of both TRAF-1–deficient adipocytes and macrophages. In human obesity, TRAF-1–dependent genes were upregulated. Conclusions: Enhancing TRAF-1–dependent inflammatory pathways in a gain-of-function approach protected from metabolic derangements in diet-induced obesity. These findings identify TRAF-1 as a regulator of dysmetabolism in mice and humans and question the pathogenic role of chronic inflammation in metabolism.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.117.312055
    RVK:
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    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 1467838-X
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  • 3
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    Abstract 44: Failure of Protective Autoimmunity in Mouse and Human Atherosclerosis
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 37, No. suppl_1 ( 2017-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 37, No. suppl_1 ( 2017-05)
    Abstract: Background: In atherosclerosis, CD4 + T helper cells recognize auto-antigens including ApoB, the main protein in low-density lipoprotein (LDL). However, atherosclerosis-specific, auto-reactive CD4 + T cells have not been detected in vivo , and their function is unknown. Methods and Results: We have previously identified peptides derived from mouse ApoB that bind with high affinity to the MHC class II molecule of C57BL/6 mice (I-A b ). We designed and validated a new multimer of a recombinant MHC-II molecule fused to one ApoB auto-epitopes, P6 (TGAYSNASSTESASY, P6:I-A b ), that enabled detection of low-affinity, P6-reactive CD4 + T cells. Using this P6:I-A b multimer, we identified ApoB-reactive CD4 + T cells in healthy, young C57BL/6 mice that were predominately differentiated T-regulatory cells (T regs ) and expressed IL-10, a known atheroprotective cytokine. This population was detectable in lymph nodes and already showed a memory phenotype in young animals without atherosclerosis. In Apoe -/- mice, adoptively transferred ApoB P6-specific T regs accumulated in the aorta and draining lymph nodes and gave rise to pathogenic T H 1 and T H 17 cells. This phenotypic switch was caused by enhanced plasticity of antigen-specific T regs as evidenced by multiple clusters of intermediate T reg -T eff phenotypes in single cell RNA sequencing of 4485 antigen-specific CD4 + T cells. In the plaque, many T cells were ex-T regs as identified by a FoxP3 lineage tracker mouse, suggesting that atherosclerosis-specific CD4 + T cells lost their regulatory capacity. Vaccination with P6 maintained a protective phenotype in antigen-specific T regs and protected from atherosclerosis. In humans, ApoB-specific CD4 + T cells from atherosclerotic patients showed the same cytokine patterns found in mouse CD4 + T cells, suggesting that autoimmunity to ApoB is protective first, but later gives rise to a pathogenic CD4 + T cell response that aggravates atherosclerosis. Conclusion: Protective T-regulatory cells recognizing peptide antigens of ApoB exist in naïve mice, protect against atherosclerosis, but convert into pathogenic T H 1 and -17 cells during the natural course of disease in mice and humans. These results call for immunomodulatory therapies to maintain protective autoimmunity.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.37.suppl_1.44
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
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  • 4
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    Abstract 413: Designed Ankyrin Repeat Proteins Against Activation Specific Binding Sites of The Leukocyte Integrin αmβ2: Novel Strategies in Vascular Inflammation
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 35, No. suppl_1 ( 2015-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. suppl_1 ( 2015-05)
    Abstract: Introduction: Vascular inflammation is the underlying condition of several cardiovascular diseases and is mainly mediated by activated leukocytes. The leukocyte integrin αMβ2 with its activation specific epitope (I domain) is strongly involved in leukocyte adhesion to endothelial cells and thus represents an interesting therapeutic target. Designed Ankyrin Repeat Proteins (DARPins) are a novel class of linear, thermostable, highly specific recombinant binding proteins that overcome several limitations of immunoglobulins. Hypothesis: DARPins selected against the mouse I domain (mId) of αMβ2 bind specifically to activated leukocytes and can be used as a novel diagnostic tool as well as a therapeutic, anti-inflammatory agent. Methods: Using phage display, binding proteins were selected against recombinant I domain. Specific binding behavior to only activated leukocytes was assessed in FACS. Docking studies were used to define specific interaction sites of selected DARPins with the I domain. Therapeutic, anti-inflammatory effects of anti-mId DARPins was assessed in a sepsis mouse model. Results: DARPins selected against the I domain bind in FACS specifically to activated monocytes (activated vs. non-activated 61±4 % vs. 19±6 %, p 〈 0.05). Docking studies revealed amino acid positions responsible for the specific binding behavior. Mutagenesis of these residues showed significantly reduced binding of the mutated DARPin using FACS analysis (anti-mId DARPin vs. mutated anti-mId DARPin 61±4 vs. 29±7, p 〈 0.05) proving that binding of the wild type DARPin to its target is specific. Furthermore, anti- I domain DARPins showed anti-inflammatory effects in a mouse sepsis model (peritoneal cells: anti-mId DARPin vs control: 2,049±189 103/ml vs. 3,382±213 103/ml, p 〈 0.01). Conclusions: DARPins selected against the I domain of αMβ2 bind specifically to activated leukocytes and inhibit leukocyte function as a new class of anti-inflammatory agents under in vivo conditions.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.35.suppl_1.413
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
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  • 5
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    Abstract 047: The Signaling Adapter Tumor-Necrosis Receptor Associated Factor 1 (TRAF-1) Regulates Thrombosis and Haemostasis in Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 38, No. Suppl_1 ( 2018-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 38, No. Suppl_1 ( 2018-05)
    Abstract: Background: The signaling pathways linking inflammatory and thrombotic circuits in platelets are only poorly understood. Here, we tested the role of the inflammatory signaling adapter TRAF-1, which bundles TNF-, TLR, and IL1-signaling, in platelets. Methods and Results: To establish a role for platelet expressed TRAF-1, we verified its expression in in vitro generated mouse thrombi in immunohistochemistry and western blot. Blood clots generated from blood of Traf1 -deficient mice were smaller, suggestive of a defective plasmatic coagulation. In accord, tail bleeding time was increased by ~4-fold in Traf1 -/- mice. Genetically chimeric mice generated by bone marrow transplantations with a selective deficiency of Traf1 in bone-marrow-derived leukocytes showed no changes in bleeding time, suggesting that the prolonged bleeding time in Traf1 -/- mice was regulated by vascular/stromal cells. In a gene expression array of Traf1 -/- endothelial cells, several factors that regulate coagulation, including fibrinogen, tumor-homing peptide (F3), and Von Willebrand factor (vWF) were reduced. In addition to this vascular phenotype, expression of P-selectin and the activation epitope Jon/A induced by in vitro ADP and thrombin stimulation was reduced in TRAF-1-deficient platelets. As a consequence, in vivo thrombus-generation in the mesenterium was delayed with an enhanced rate of emboli in Traf1 -/- mice – an effect that was confirmed in mice transferred with TRAF1 -/- platelets, and in mice with a selective deficiency of Traf1 in bone-marrow-derived cells. Finally, we demonstrate TRAF-1 protein expression in human coronary thrombi and the presence of TRAF1 -transcripts in RNA-sequencing of human platelets. TRAF1 -mRNA expression was down-regulated in collagen and TRAP stimulated human platelets and correlated with the gene expression of several upstream platelet-receptors, including EDA2R , RELT , and CD137. Conclusion: We present the novel finding that the pro-inflammatory signaling adapter TRAF-1 is expressed in mouse and human thrombi and participates in coagulation and thrombosis by vascular and platelet-mediated pathways. These findings emphasize the connection of inflammatory signaling and haemostasis.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.38.suppl_1.047
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
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  • 6
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    P2Y 6 Deficiency Limits Vascular Inflammation and Atherosclerosis in Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 34, No. 10 ( 2014-10), p. 2237-2245
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. 10 ( 2014-10), p. 2237-2245
    Abstract: Nucleotides such as ATP, ADP, UTP, and UDP serve as proinflammatory danger signals via purinergic receptors on their release to the extracellular space by activated or dying cells. UDP binds to the purinergic receptor Y 6 (P2Y 6 ) and propagates vascular inflammation by inducing the expression of chemokines such as monocyte chemoattractant protein 1, interleukin-8, or its mouse homologsCCL1 (chemokine [C-C motif] ligand 1)/keratinocyte chemokine, CXCL2 (chemokine [C-X-C motif] ligand 2)/macrophage inflammatory protein 2, and CXCL5 (chemokine [C-X-C motif] ligand 5)/LIX, and adhesion molecules such as vascular cell adhesion molecule 1 and intercellular cell adhesion molecule 1. Thus, P2Y 6 contributes to leukocyte recruitment and inflammation in conditions such as allergic asthma or sepsis. Because atherosclerosis is a chronic inflammatory disease driven by leukocyte recruitment to the vessel wall, we hypothesized a role of P2Y 6 in atherogenesis. Approach and Results— Intraperitoneal stimulation of wild-type mice with UDP induced rolling and adhesion of leukocytes to the vessel wall as assessed by intravital microscopy. This effect was not present in P2Y 6 -deficient mice. Atherosclerotic aortas of low-density lipoprotein receptor–deficient mice consuming high-cholesterol diet for 16 weeks expressed significantly more transcripts and protein of P2Y 6 than respective controls. Finally, P2Y 6 −/− /low-density lipoprotein receptor–deficient mice consuming high-cholesterol diet for 16 weeks developed significantly smaller atherosclerotic lesions compared with P2Y 6 +/+ /low-density lipoprotein receptor–deficient mice. Bone marrow transplantation identified a crucial role of P2Y 6 on vascular resident cells, most likely endothelial cells, on leukocyte recruitment and atherogenesis. Atherosclerotic lesions of P2Y 6 -deficient mice contained fewer macrophages and fewer lipids as determined by immunohistochemistry. Mechanistically, RNA expression of vascular cell adhesion molecule 1 and interleukin-6 was decreased in these lesions and P2Y 6 -deficient macrophages took up less modified low-density lipoprotein cholesterol. Conclusions— We show for the first time that P2Y 6 deficiency limits atherosclerosis and plaque inflammation in mice.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.114.303585
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
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  • 7
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    Extracellular ATP Induces Vascular Inflammation and Atherosclerosis via Purinergic Receptor Y 2 in Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 36, No. 8 ( 2016-08), p. 1577-1586
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. 8 ( 2016-08), p. 1577-1586
    Abstract: A solid body of evidence supports a role of extracellular ATP and its P2 receptors in innate and adaptive immunity. It promotes inflammation as a danger signal in various chronic inflammatory diseases. Thus, we hypothesize contribution of extracellular ATP and its receptor P2Y 2 in vascular inflammation and atherosclerosis. Approach and Results— Extracellular ATP induced leukocyte rolling, adhesion, and migration in vivo as assessed by intravital microscopy and in sterile peritonitis. To test the role of extracellular ATP in atherosclerosis, ATP or saline as control was injected intraperitoneally 3× a week in low-density lipoprotein receptor −/− mice consuming high cholesterol diet. Atherosclerosis significantly increased after 16 weeks in ATP-treated mice (n=13; control group, 0.26 mm2; ATP group, 0.33 mm2; P =0.01). To gain into the role of ATP-receptor P2Y 2 in ATP-induced leukocyte recruitment, ATP was administered systemically in P2Y 2 -deficient or P2Y 2 -competent mice. In P2Y 2 -deficient mice, the ATP-induced leukocyte adhesion was significantly reduced as assessed by intravital microscopy. P2Y 2 expression in atherosclerosis was measured by real-time polymerase chain reaction and immunohistochemistry and demonstrates an increased expression mainly caused by influx of P2Y 2 -expressing macrophages. To investigate the functional role of P2Y 2 in atherogenesis, P2Y 2 -deficient low-density lipoprotein receptor −/− mice consumed high cholesterol diet. After 16 weeks, P2Y 2 -deficient mice showed significantly reduced atherosclerotic lesions with decreased macrophages compared with P2Y 2 -competent mice (n=11; aortic arch: control group, 0.25 mm 2 ; P2Y 2 -deficient, 0.14 mm2; P =0.04). Mechanistically, atherosclerotic lesions from P2Y 2 -deficient mice expressed less vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 RNA. Conclusions— We show that extracellular ATP induces vascular inflammation and atherosclerosis via activation of P2Y 2 .
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.115.307397
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
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  • 8
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    Pathogenic Autoimmunity in Atherosclerosis Evolves From Initially Protective Apolipoprotein B 100 –Reactive CD4 + T-Regulatory Cells
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Circulation Vol. 142, No. 13 ( 2020-09-29), p. 1279-1293
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 142, No. 13 ( 2020-09-29), p. 1279-1293
    Abstract: Throughout the inflammatory response that accompanies atherosclerosis, autoreactive CD4 + T-helper cells accumulate in the atherosclerotic plaque. Apolipoprotein B 100 (apoB), the core protein of low-density lipoprotein, is an autoantigen that drives the generation of pathogenic T-helper type 1 (T H 1) cells with proinflammatory cytokine secretion. Clinical data suggest the existence of apoB-specific CD4 + T cells with an atheroprotective, regulatory T cell (T reg ) phenotype in healthy individuals. Yet, the function of apoB-reactive T regs and their relationship with pathogenic T H 1 cells remain unknown. Methods: To interrogate the function of autoreactive CD4 + T cells in atherosclerosis, we used a novel tetramer of major histocompatibility complex II to track T cells reactive to the mouse self-peptide apo B 978-993 (apoB + ) at the single-cell level. Results: We found that apoB + T cells build an oligoclonal population in lymph nodes of healthy mice that exhibit a T reg -like transcriptome, although only 21% of all apoB + T cells expressed the T reg transcription factor FoxP3 (Forkhead Box P3) protein as detected by flow cytometry. In single-cell RNA sequencing, apoB + T cells formed several clusters with mixed T H signatures that suggested overlapping multilineage phenotypes with pro- and anti-inflammatory transcripts of T H 1, T helper cell type 2 (T H 2), and T helper cell type 17 (T H 17), and of follicular-helper T cells. ApoB + T cells were increased in mice and humans with atherosclerosis and progressively converted into pathogenic T H 1/T H 17-like cells with proinflammatory properties and only a residual T reg transcriptome. Plaque T cells that expanded during progression of atherosclerosis consistently showed a mixed T H 1/T H 17 phenotype in single-cell RNA sequencing. In addition, we observed a loss of FoxP3 in a fraction of apoB + T regs in lineage tracing of hyperlipidemic Apoe –/– mice. In adoptive transfer experiments, converting apoB + T regs failed to protect from atherosclerosis. Conclusions: Our results demonstrate an unexpected mixed phenotype of apoB-reactive autoimmune T cells in atherosclerosis and suggest an initially protective autoimmune response against apoB with a progressive derangement in clinical disease. These findings identify apoB autoreactive T regs as a novel cellular target in atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.119.042863
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
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  • 9
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    Abstract 597: Diet-induced Obesity Requires Signalling Through Tumor Necrosis Factor Receptor-associated Factor 1 (TRAF-1) in Adipocytes
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 36, No. suppl_1 ( 2016-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. suppl_1 ( 2016-05)
    Abstract: Background: Accumulation of inflammatory leukocytes is a prerequisite of adipose tissue inflammation during cardio-metabolic disease. We recently reported that a genetic deficiency of the intracellular signalling adaptor TRAF-1 attenuates inflammatory cell recruitment and vascular inflammation in atherosclerosis. Here, we tested the contribution of TRAF-1 to diet-induced obesity (DIO) in mice. Methods and Results: To test the association of TRAFs and obesity we screened for expression of different TRAFs in adipose tissue. We found an up-regulation of TRAF-1 mRNA in obese mouse and human adipose tissue, resulting from higher gene expression in adipocytes, but not in adipose tissue macrophages. To test a functional relevance of TRAF-1 signalling in obesity, WT or TRAF-1 -/- mice consumed a high fat diet HFD for 20 weeks. Surprisingly, genetic deficiency of TRAF-1 abolished diet-induced weight gain by supressing peripheral fat depositions. Consequently, TRAF-1 -/- mice demonstrated ameliorated glucose levels after glucose and insulin tolerance tests and dampened insulin signalling. Consistently, we also found reduced accumulation of adipose tissue macrophages. Mechanistically, TRAF-1 -/- mice demonstrated no differences in basic energy metabolism, such as in energy expenditure. However, TRAF-1 -/- adipocytes had higher expression of Adipose Triglyceride Lipase (ATGL) and Hormone-sensitive Lipase (HSL), suggesting increased lipid breakdown in adipocytes. In accord, plasma levels of free fatty acids were higher, while leptin levels were reduced in TRAF-1 -/- mice. Finally, in a collective of patients with a high prevalence of the metabolic syndrome, TRAF-1 expression correlated with the metabolic syndrome, suggesting clinical relevance of our findings. Conclusion: We present the novel finding that the signalling adapter TRAF-1 correlates with obesity in mice and humans. Genetic deficiency of TRAF-1 attenuates diet-induced obesity by increasing lipolysis in adipocytes. These findings identify TRAF-1 as a novel therapeutic target in obesity and adipose-tissue inflammation.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.36.suppl_1.597
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
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  • 10
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    Abstract 362: Acute Exposure to Air Pollution Aggravates Acute Myocardial Infarction and Subsequent Ischemic Heart Failure in Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 36, No. suppl_1 ( 2016-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. suppl_1 ( 2016-05)
    Abstract: Background: Clinical, but not experimental evidence has suggested that exposure to air pollution particulate matter (PM) aggravates myocardial infarction (MI) in humans. Here, we aimed to describe mechanisms and consequences of an acute PM exposure in an experimental mouse model of MI. Methods and Results: C57BL/6J mice were exposed to an air pollution particulate matter (PM) surrogate (Residual Oil Fly Ash) by intranasal installation, prior to surgical permanent ligation of the left anterior descending coronary artery (LAD). Mice exposed to PM showed exaggerated ischemic heart failure with decreased fractional shortening and diastolic dilatation in echocardiography 6 month after MI. Histological analysis demonstrated an increase in the infarct area by 45 ± 12 % and enhanced inflammatory cell recruitment into the myocardium of PM-exposed mice 6 days after MI. Augmented cell recruitment was caused by increased activation of circulating myeloid and vascular endothelial cells. Consistently, PM exposure increased leukocyte recruitment a model of sterile peritonitis and in intravital microscopy. Mechanistically, PM exposure potentiated levels of circulating pro-inflammatory cytokines, such as of TNF-α by up to 327 ± 100 %. Increased activation of endothelial cells and leukocytes could be reversed by TNF-α antibody blockade. We identified alveolar macrophages as primary source of elevated cytokine production. Accordingly, specific in vivo depletion of lung macrophages by clodronate inhibited cytokine secretion, abolished leukocyte recruitment in intravital microscopy, and protected from cardiac inflammation after simultaneous PM exposure. Conversely, lymphocyte-free Rag1 -/- mice where susceptible to PM, indicating that alveolar macrophages, but not lymphocytes, are the cause of the systemic inflammatory response following air pollution. Conclusion: Our data demonstrate that an acute exposure to environmental PM worsens MI and its clinical outcome in mice. These findings provide a novel functional link between air pollution and inflammatory pathways, and emphasize the importance of environmental factors in cardiovascular disease.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.36.suppl_1.362
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
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