Publications by authors named "Bianca Dufner"

13 Publications

  • Page 1 of 1

Myeloid cell-specific Irf5 deficiency stabilizes atherosclerotic plaques in Apoe mice.

Mol Metab 2021 May 12;53:101250. Epub 2021 May 12.

University Heart Center, Department of Cardiology and Angiology I, University of Freiburg and Faculty of Medicine, 55 Hugstetter St, 79106, Freiburg, Germany. Electronic address:

Objective: Interferon regulatory factor (IRF) 5 is a transcription factor known for promoting M1 type macrophage polarization in vitro. Given the central role of inflammatory macrophages in promoting atherosclerotic plaque progression, we hypothesize that myeloid cell-specific deletion of IRF5 is protective against atherosclerosis.

Methods: Female ApoeLysmIrf5 and ApoeIrf5 mice were fed a high-cholesterol diet for three months. Atherosclerotic plaque size and compositions as well as inflammatory gene expression were analyzed. Mechanistically, IRF5-dependent bone marrow-derived macrophage cytokine profiles were tested under M1 and M2 polarizing conditions. Mixed bone marrow chimeras were generated to determine intrinsic IRF5-dependent effects on macrophage accumulation in atherosclerotic plaques.

Results: Myeloid cell-specific Irf5 deficiency blunted LPS/IFNγ-induced inflammatory gene expression in vitro and in the atherosclerotic aorta in vivo. While atherosclerotic lesion size was not reduced in myeloid cell-specific Irf5-deficient Apoe mice, plaque composition was favorably altered, resembling a stable plaque phenotype with reduced macrophage and lipid contents, reduced inflammatory gene expression and increased collagen deposition alongside elevated Mertk and Tgfβ expression. Irf5-deficient macrophages, when directly competing with wild type macrophages in the same mouse, were less prone to accumulate in atherosclerotic lesion, independent of monocyte recruitment. Irf5-deficient monocytes, when exposed to oxidized low density lipoprotein, were less likely to differentiate into macrophage foam cells, and Irf5-deficient macrophages proliferated less in the plaque.

Conclusion: Our study provides genetic evidence that selectively altering macrophage polarization induces a stable plaque phenotype in mice.
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http://dx.doi.org/10.1016/j.molmet.2021.101250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178123PMC
May 2021

Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering.

Basic Res Cardiol 2020 12 9;115(6):78. Epub 2020 Dec 9.

Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany.

Statins induce plaque regression characterized by reduced macrophage content in humans, but the underlying mechanisms remain speculative. Studying the translational APOE*3-Leiden.CETP mouse model with a humanized lipoprotein metabolism, we find that systemic cholesterol lowering by oral atorvastatin or dietary restriction inhibits monocyte infiltration, and reverses macrophage accumulation in atherosclerotic plaques. Contrary to current believes, none of (1) reduced monocyte influx (studied by cell fate mapping in thorax-shielded irradiation bone marrow chimeras), (2) enhanced macrophage egress (studied by fluorescent bead labeling and transfer), or (3) atorvastatin accumulation in murine or human plaque (assessed by mass spectrometry) could adequately account for the observed loss in macrophage content in plaques that undergo phenotypic regression. Instead, suppression of local proliferation of macrophages dominates phenotypic plaque regression in response to cholesterol lowering: the lower the levels of serum LDL-cholesterol and lipid contents in murine aortic and human carotid artery plaques, the lower the rates of in situ macrophage proliferation. Our study identifies macrophage proliferation as the predominant turnover determinant and an attractive target for inducing plaque regression.
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http://dx.doi.org/10.1007/s00395-020-00838-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725697PMC
December 2020

Proinflammatory α-Adrenergic Neuronal Regulation of Splenic IFN-γ, IL-6, and TGF-β of Mice from Day 15 onwards in Arthritis.

Neuroimmunomodulation 2020 1;27(1):58-68. Epub 2020 Jul 1.

Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine, University Hospital, Regensburg, Germany.

Introduction: In arthritic mice, a sympathetic influence is proinflammatory from the time point of immunization until the onset of disease (days 0-32), but reasons are unknown. Disruption of the major anti-inflammatory pathway through Gαs-coupled receptors probably play a role. For example, noradrenaline cannot operate via anti-inflammatory β2-adrenoceptors but through proinflammatory α1/2-ad-renoceptors. This might happen, first, through a loss of sympathetic nerve fibers in inflamed tissue with low neurotransmitter levels (noradrenaline only binds to high-affinity α-adrenoceptors) and, second, through an alteration in G-protein receptor coupling with a predominance of α-adrenergic signaling. We hypothesized that both mechanisms play a role in the course of collagen type II-induced arthritis (CIA) in the spleen in mice.

Methods: In CIA mice, nerve fiber density in the spleen was quantified by immunohistochemistry techniques. The functional impact of sympathetic nerve fibers in the spleen was studied by a micro-superfusion technique of spleen slices with a focus on the secretion of IFN-γ and IL-6 (proinflammatory) and TGF-β (anti-inflammatory).

Results: During CIA, sympathetic nerve fibers get increasingly lost from day14 until day 55 after immunization. The influence of electrically released noradrenaline diminishes in the course of arthritis. At all investigated time points (days 14, 32, and 55), only proinflammatory neuronal α-adrenergic effects on cytokine secretion were demonstrated (i.e., stimulation of IFN-γ and IL-6 and inhibition of TGF-β).

Conclusion: Sympathetic nerve fibers are rapidly lost in the spleen, and only proinflammatory α-adrenergic neuronal regulation of cytokine secretion takes place throughout the course of arthritis. These results support a predominance of a proinflammatory α-adrenergic sympathetic influence in arthritis.
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http://dx.doi.org/10.1159/000508109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446300PMC
July 2021

A thyroid hormone network exists in synovial fibroblasts of rheumatoid arthritis and osteoarthritis patients.

Sci Rep 2019 09 13;9(1):13235. Epub 2019 Sep 13.

Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Dept. of Internal Medicine, University Hospital Regensburg, Regensburg, Germany.

While patients with rheumatoid arthritis (RA) sometimes demonstrate thyroidal illness, the role of thyroid hormones in inflamed synovial tissue is unknown. This is relevant because thyroid hormones stimulate immunity, and local cells can regulate thyroid hormone levels by deiodinases (DIO). The study followed the hypothesis that elements of a thyroid hormone network exist in synovial tissue. In 12 patients with RA and 32 with osteoarthritis (OA), we used serum, synovial fluid, synovial tissue, and synovial fibroblasts (SF) in order to characterize the local thyroid hormone network using ELISAs, immunohistochemistry, imaging methods, tissue superfusion studies, cell-based ELISAs, flow cytometry, and whole genome expression profiling. Serum/synovial fluid thyroid hormone levels were similar in RA and OA (inclusion criteria: no thyroidal illness). The degradation product termed reverse triiodothyronine (reverse T3) was much lower in serum compared to synovial fluid indicating biodegradation of thyroid hormones in the synovial environment. Superfusion experiments with synovial tissue also demonstrated biodegradation, particularly in RA. Cellular membrane transporters of thyroid hormones, DIOs, and thyroid hormone receptors were present in tissue and SF. Density of cells positive for degrading DIOs were higher in RA than OA. TNF increased protein expression of degrading DIOs in RASF and OASF. Gene expression studies of RASF revealed insignificant gene regulation by bioactive T3. RA and OA synovial tissue/SF show a local thyroid hormone network. Thyroid hormones undergo strong biodegradation in synovium. While bioactive T3 does not influence SF gene expression, SF seem to have a relay function for thyroid hormones.
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http://dx.doi.org/10.1038/s41598-019-49743-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744488PMC
September 2019

Inflammatory Pathways Regulated by Tumor Necrosis Receptor-Associated Factor 1 Protect From Metabolic Consequences in Diet-Induced Obesity.

Circ Res 2018 03 22;122(5):693-700. Epub 2018 Jan 22.

From the Cardiology and Angiology I, University Heart Center and Medical Center (N.A.M., C.C., B.D., N.H., K.P., T.M., F.W., P.S., I.H., T.H., C.v.z.M., C.B., A.Z., D.W.), Faculty of Biology (N.A.M.), Department of Radiology, Medical Physics, Medical Center (D.v.E.), Hematology and Oncology (D.P.), and Department of Urology (R.S.), University of Freiburg, Germany; Inflammation Biology, La Jolla Institute for Allergy and Immunology, CA (K.B., A.B.P., E.E., K.L., D.W.); Neurosurgery, University of Erlangen, Germany (B.S.); Center for Cardiovascular Research (U.K.) and Department of Endocrinology & Metabolism, Center for Cardiovascular Research (CCR), Germany (S.B.), Charité-Universitätsmedizin Berlin, Germany; and Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Partner Site Berlin, Germany (S.B.).

Rationale: 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.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.312055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834385PMC
March 2018

Inflammation, but not recruitment, of adipose tissue macrophages requires signalling through Mac-1 (CD11b/CD18) in diet-induced obesity (DIO).

Thromb Haemost 2017 01 17;117(2):325-338. Epub 2016 Nov 17.

Prof. Dr. Karlheinz Peter, Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, P. O. Box 6492. St. Kilda Road Central, Melbourne, Victoria 8008, Australia, Tel.: +61 3 8532 1490, Fax: +61 3 8532 1100, E-mail:

Cell accumulation is a prerequisite for adipose tissue inflammation. The leukocyte integrin Mac-1 (CD11b/CD18, αβ) is a classic adhesion receptor critically regulating inflammatory cell recruitment. Here, we tested the hypothesis that a genetic deficiency and a therapeutic modulation of Mac-1 regulate adipose tissue inflammation in a mouse model of diet-induced obesity (DIO). C57Bl6/J mice genetically deficient (Mac-1) or competent for Mac-1 (WT) consumed a high fat diet for 20 weeks. Surprisingly, Mac-1 mice presented with increased diet-induced weight gain, decreased insulin sensitivity in skeletal muscle and in the liver in insulin-clamps, insulin secretion deficiency and elevated glucose levels in fasting animals, and dyslipidaemia. Unexpectedly, accumulation of adipose tissue macrophages (ATMs) was unaffected, while gene expression indicated less inflamed adipose tissue and macrophages in Mac-1 mice. In contrast, inflammatory gene expression at distant locations, such as in skeletal muscle, was not changed. Treatment of ATMs with an agonistic anti-Mac-1 antibody, M1/70, induced pro-inflammatory genes in cell culture. In vivo, treatment with M1/70 induced a hyper-inflammatory phenotype with increased expression of IL-6 and MCP-1, whereas accumulation of ATMs did not change. Finally, inhibition of Mac-1's adhesive interaction to CD40L by the peptide inhibitor cM7 did not affect myeloid cell accumulation in adipose tissue. We present the surprising finding that adhesive properties of the leukocyte integrin Mac-1 are not required for macrophage accumulation in adipose tissue. Instead, Mac-1 modulates inflammatory gene expression in macrophages. These findings question the net effect of integrin blockade in cardio-metabolic disease.
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http://dx.doi.org/10.1160/TH16-07-0553DOI Listing
January 2017

Extracellular ATP Induces Vascular Inflammation and Atherosclerosis via Purinergic Receptor Y2 in Mice.

Arterioscler Thromb Vasc Biol 2016 08 23;36(8):1577-86. Epub 2016 Jun 23.

From the Atherogenesis Research Group, University Heart Center Freiburg, Department of Cardiology and Angiology I (P.S., S.G., A.P., A.H., N.A.M., F.Ü., N.H., B.D., L.S., T.M., D.W., I.H., F.W., J.R., C.v.z.M., C.B., A.Z.) and Department of Pneumology (S.C., K.A., A.Z., M.I.), University of Freiburg, Freiburg, Germany.

Objective: 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 P2Y2 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 P2Y2 in ATP-induced leukocyte recruitment, ATP was administered systemically in P2Y2-deficient or P2Y2-competent mice. In P2Y2-deficient mice, the ATP-induced leukocyte adhesion was significantly reduced as assessed by intravital microscopy. P2Y2 expression in atherosclerosis was measured by real-time polymerase chain reaction and immunohistochemistry and demonstrates an increased expression mainly caused by influx of P2Y2-expressing macrophages. To investigate the functional role of P2Y2 in atherogenesis, P2Y2-deficient low-density lipoprotein receptor(-/-) mice consumed high cholesterol diet. After 16 weeks, P2Y2-deficient mice showed significantly reduced atherosclerotic lesions with decreased macrophages compared with P2Y2-competent mice (n=11; aortic arch: control group, 0.25 mm(2); P2Y2-deficient, 0.14 mm2; P=0.04). Mechanistically, atherosclerotic lesions from P2Y2-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 P2Y2.
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http://dx.doi.org/10.1161/ATVBAHA.115.307397DOI Listing
August 2016

Acute exposure to air pollution particulate matter aggravates experimental myocardial infarction in mice by potentiating cytokine secretion from lung macrophages.

Basic Res Cardiol 2016 07 30;111(4):44. Epub 2016 May 30.

Atherogenesis Research Group, Cardiology and Angiology I, University Heart Center, University of Freiburg, Hugstetterstrasse 55, 79106, Freiburg, Germany.

Clinical, but not experimental evidence has suggested that air pollution particulate matter (PM) aggravates myocardial infarction (MI). Here, we aimed to describe mechanisms and consequences of PM exposure in an experimental model of MI. C57BL/6J mice were challenged with a PM surrogate (Residual Oil Fly Ash, ROFA) by intranasal installation before MI was induced by permanent ligation of the left anterior descending coronary artery. Histological analysis of the myocardium 7 days after MI demonstrated an increase in infarct area and enhanced inflammatory cell recruitment in ROFA-exposed mice. Mechanistically, ROFA exposure increased the levels of the circulating pro-inflammatory cytokines TNF-α, IL-6, and MCP-1, activated myeloid and endothelial cells, and enhanced leukocyte recruitment to the peritoneal cavity and the vascular endothelium. Notably, these effects on endothelial cells and circulating leukocytes could be reversed by neutralizing anti-TNF-α treatment. We identified alveolar macrophages as the primary source of elevated cytokine production after PM exposure. Accordingly, in vivo depletion of alveolar macrophages by intranasal clodronate attenuated inflammation and cell recruitment to infarcted tissue of ROFA-exposed mice. Taken together, our data demonstrate that exposure to environmental PM induces the release of inflammatory cytokines from alveolar macrophages which directly worsens the course of MI in mice. These findings uncover a novel link between air pollution PM exposure and inflammatory pathways, highlighting the importance of environmental factors in cardiovascular disease.
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http://dx.doi.org/10.1007/s00395-016-0562-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886146PMC
July 2016

Atheroprotection through SYK inhibition fails in established disease when local macrophage proliferation dominates lesion progression.

Basic Res Cardiol 2016 Mar 18;111(2):20. Epub 2016 Feb 18.

Department of Cardiology and Angiology I, University Heart Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.

Macrophages in the arterial intima sustain chronic inflammation during atherogenesis. Under hypercholesterolemic conditions murine Ly6C(high) monocytes surge in the blood and spleen, infiltrate nascent atherosclerotic plaques, and differentiate into macrophages that proliferate locally as disease progresses. Spleen tyrosine kinase (SYK) may participate in downstream signaling of various receptors that mediate these processes. We tested the effect of the SYK inhibitor fostamatinib on hypercholesterolemia-associated myelopoiesis and plaque formation in Apoe(-/-) mice during early and established atherosclerosis. Mice consuming a high cholesterol diet supplemented with fostamatinib for 8 weeks developed less atherosclerosis. Histologic and flow cytometric analysis of aortic tissue showed that fostamatinib reduced the content of Ly6C(high) monocytes and macrophages. SYK inhibition limited Ly6C(high) monocytosis through interference with GM-CSF/IL-3 stimulated myelopoiesis, attenuated cell adhesion to the intimal surface, and blocked M-CSF stimulated monocyte to macrophage differentiation. In Apoe(-/-) mice with established atherosclerosis, however, fostamatinib treatment did not limit macrophage accumulation or lesion progression despite a significant reduction in blood monocyte counts, as lesional macrophages continued to proliferate. Thus, inhibition of hypercholesterolemia-associated monocytosis, monocyte infiltration, and differentiation by SYK antagonism attenuates early atherogenesis but not established disease when local macrophage proliferation dominates lesion progression.
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http://dx.doi.org/10.1007/s00395-016-0535-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759214PMC
March 2016

An Emerging Approach for Parallel Quantification of Intracellular Protozoan Parasites and Host Cell Characterization Using TissueFAXS Cytometry.

PLoS One 2015 21;10(10):e0139866. Epub 2015 Oct 21.

Institute of Immunology, University of Regensburg, Regensburg, Germany.

Characterization of host-pathogen interactions is a fundamental approach in microbiological and immunological oriented disciplines. It is commonly accepted that host cells start to change their phenotype after engulfing pathogens. Techniques such as real time PCR or ELISA were used to characterize the genes encoding proteins that are associated either with pathogen elimination or immune escape mechanisms. Most of such studies were performed in vitro using primary host cells or cell lines. Consequently, the data generated with such approaches reflect the global RNA expression or protein amount recovered from all cells in culture. This is justified when all host cells harbor an equal amount of pathogens under experimental conditions. However, the uptake of pathogens by phagocytic cells is not synchronized. Consequently, there are host cells incorporating different amounts of pathogens that might result in distinct pathogen-induced protein biosynthesis. Therefore, we established a technique able to detect and quantify the number of pathogens in the corresponding host cells using immunofluorescence-based high throughput analysis. Paired with multicolor staining of molecules of interest it is now possible to analyze the infection profile of host cell populations and the corresponding phenotype of the host cells as a result of parasite load.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0139866PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619545PMC
June 2016

P2Y6 deficiency limits vascular inflammation and atherosclerosis in mice.

Arterioscler Thromb Vasc Biol 2014 Oct 7;34(10):2237-45. Epub 2014 Aug 7.

From the Atherogenesis Research Group, University Heart Center, Cardiology and Angiology I, University of Freiburg, Freiburg, Germany (P.S., A.P., N.A.M., S.H., T.M., D.W., B.D., N.H., L.S., J.R., C.v.z.M., C.B., A.Z.); and Department of Pneumology, University of Freiburg, Freiburg, Germany (C.K.A., M.G., S.C., M.I.).

Objective: 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 Y6 (P2Y6) 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, P2Y6 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 P2Y6 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 P2Y6-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 P2Y6 than respective controls. Finally, P2Y6 (-/-)/low-density lipoprotein receptor-deficient mice consuming high-cholesterol diet for 16 weeks developed significantly smaller atherosclerotic lesions compared with P2Y6 (+/+)/low-density lipoprotein receptor-deficient mice. Bone marrow transplantation identified a crucial role of P2Y6 on vascular resident cells, most likely endothelial cells, on leukocyte recruitment and atherogenesis. Atherosclerotic lesions of P2Y6-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 P2Y6-deficient macrophages took up less modified low-density lipoprotein cholesterol.

Conclusions: We show for the first time that P2Y6 deficiency limits atherosclerosis and plaque inflammation in mice.
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http://dx.doi.org/10.1161/ATVBAHA.114.303585DOI Listing
October 2014

Coinhibitory suppression of T cell activation by CD40 protects against obesity and adipose tissue inflammation in mice.

Circulation 2014 Jun 24;129(23):2414-25. Epub 2014 Mar 24.

From the Atherogenesis Research Group, University Heart Center (D.W., F.J., N.A.M., E.N.B., N.H., B.D., A.O.R., C.C., L.N., B.R., A.W., L.S., A.P., A.L., S.P.H., P.S., I.H., F.W., C.v.z.M., C.B., A.Z.) and Institute for Medical Microbiology and Hygiene, Department of Immunology (P.A.), University of Freiburg, Freiburg, Germany; Atherothrombosis and Vascular Biology (F.J., J.R., Y.C.C., C.C., N.B., K.P.) and Cellular and Molecular Metabolism (M.A.F.), Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Department of Diagnostic Radiology Medical Physics, University Hospital Freiburg, Freiburg, Germany (D.v.E.); Department of Laboratory Medicine, Medical University of Vienna and Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria (C.J.B.); Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain (N.V.); and Brigham and Women's Hospital, Cardiovascular Medicine, Harvard Medical School, Boston, MA (P.L.).

Background: 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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.113.008055DOI Listing
June 2014

CD40L deficiency attenuates diet-induced adipose tissue inflammation by impairing immune cell accumulation and production of pathogenic IgG-antibodies.

PLoS One 2012 8;7(3):e33026. Epub 2012 Mar 8.

Atherogenesis Research Group, Department of Cardiology, University of Freiburg, Freiburg, Germany.

Background: Adipose tissue inflammation fuels the metabolic syndrome. We recently reported that CD40L--an established marker and mediator of cardiovascular disease--induces inflammatory cytokine production in adipose cells in vitro. Here, we tested the hypothesis that CD40L deficiency modulates adipose tissue inflammation in vivo.

Methodology/principal Findings: WT or CD40L(-/-) mice consumed a high fat diet (HFD) for 20 weeks. Inflammatory cell recruitment was impaired in mice lacking CD40L as shown by a decrease of adipose tissue macrophages, B-cells, and an increase in protective T-regulatory cells. Mechanistically, CD40L-deficient mice expressed significantly lower levels of the pro-inflammatory chemokine MCP-1 both, locally in adipose tissue and systemically in plasma. Moreover, levels of pro-inflammatory IgG-antibodies against oxidized lipids were reduced in CD40L(-/-) mice. Also, circulating low-density lipoproteins and insulin levels were lower in CD40L(-/-) mice. However, CD40L(-/-) mice consuming HFD were not protected from the onset of diet-induced obesity (DIO), insulin resistance, and hepatic steatosis, suggesting that CD40L selectively limits the inflammatory features of diet-induced obesity rather than its metabolic phenotype. Interestingly, CD40L(-/-) mice consuming a low fat diet (LFD) showed both, a favorable inflammatory and metabolic phenotype characterized by diminished weight gain, improved insulin tolerance, and attenuated plasma adipokine levels.

Conclusion: We present the novel finding that CD40L deficiency limits adipose tissue inflammation in vivo. These findings identify CD40L as a potential mediator at the interface of cardiovascular and metabolic disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0033026PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297623PMC
August 2012
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