Bernhard Brüne

Goethe-Universität Frankfurt am Main, Frankfurt, Hesse, Germany

Are you Bernhard Brüne?

Claim your profile

Publications (282)1326.92 Total impact

  • Circulation 06/2015; 131(22):e515-6. DOI:10.1161/CIRCULATIONAHA.114.014781 · 14.95 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Macrophages, converted to lipid-loaded foam cells, accumulate in atherosclerotic lesions. Macrophage lipid metabolism is transcriptionally regulated by peroxisome proliferator-activated receptor gamma (PPARγ), and its target gene fatty acid binding protein 4 (FABP4) accelerates the progression of atherosclerosis in mouse models. Since expression of PPARγ and FABP4 is increased upon interleukin-4 (IL-4)-induced macrophage polarization, we aimed to investigate the role of FABP4 in human IL-4-polarized macrophages. We investigated the impact of FABP4 on PPARγ-dependent gene expression in primary human monocytes differentiated to macrophages in the presence of IL-4. IL-4 increased PPARγ and its target genes lipoprotein lipase (LPL) and FABP4 compared to non-polarized or LPS/interferon γ-stimulated macrophages. LPL expression correlated with increased very low density lipoprotein (VLDL)-induced triglyceride accumulation in IL-4-polarized macrophages, which was sensitive to inhibition of lipolysis or PPARγ antagonism. Inhibition of FABP4 during differentiation using chemical inhibitors BMS309403 and HTS01037 or FABP4 siRNA decreased the expression of FABP4 and LPL, and reduced lipid accumulation in macrophages treated with VLDL. FABP4 or LPL inhibition also reduced the expression of inflammatory mediators chemokine (C-C motif) ligand 2 (CCL2) and IL-1β in response to VLDL in IL-4-polarized macrophages. PPARγ luciferase reporter assays confirmed that FABP4 supports fatty acid-induced PPARγ activation. Our findings suggest that IL-4 induces a lipid-accumulating macrophage phenotype by activating PPARγ and subsequent LPL expression. Inhibition of FABP4 decreases VLDL-induced foam cell formation, indicating that anti-atherosclerotic effects achieved by FABP4 inhibition in mouse models may be feasible in the human system as well. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Atherosclerosis 04/2015; 240(2). DOI:10.1016/j.atherosclerosis.2015.03.042 · 3.97 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Prostaglandin E2 (PGE2) favors multiple aspects of tumor development and immune evasion. Therefore, microsomal prostaglandin E synthase (mPGES-1/-2), is a potential target for cancer therapy. We explored whether inhibiting mPGES-1 in human and mouse models of breast cancer affects tumor-associated immunity. A new model of breast tumor spheroid killing by human PBMCs was developed. In this model, tumor killing required CD80 expression by tumor-associated phagocytes to trigger cytotoxic T cell activation. Pharmacological mPGES-1 inhibition increased CD80 expression, whereas addition of PGE2, a prostaglandin E2 receptor 2 (EP2) agonist, or activation of signaling downstream of EP2 reduced CD80 expression. Genetic ablation of mPGES-1 resulted in markedly reduced tumor growth in PyMT mice. Macrophages of mPGES-1-/- PyMT mice indeed expressed elevated levels of CD80 compared to their wildtype counterparts. CD80 expression in tumor-spheroid infiltrating mPGES-1-/- macrophages translated into antigen-specific cytotoxic T cell activation. In conclusion, mPGES-1 inhibition elevates CD80 expression by tumor-associated phagocytes to restrict tumor growth. We propose that mPGES-1 inhibition in combination with immune cell activation might be part of a therapeutic strategy to overcome the immunosuppressive tumor microenvironment.
    Oncotarget 03/2015; · 6.63 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumor-associated lymphangiogenesis was identified as an important clinical determinant for the prognosis of HCC and significantly influences patient survival. However, in this context little is known about regulation of lymphangiogenesis by hypoxia inducible factors. In HCC mainly HIF-1α was positively correlated with lymphatic invasion and metastasis, while a defined role of HIF-2α is missing. We created a stable knockdown of HIF-1α and HIF-2α in HepG2 cells and generated cocultures of HepG2 spheroids with embryonic bodies. This constitutes an in vitro tumor model mimicking the cancer microenvironment and allows addressing the role of distinct HIF isoforms in regulating HCC lymphangiogenesis. In cocultures with a HIF-2α knockdown lymphangiogenesis was significantly increased, while the knockdown of HIF-1α showed no effect. The HIF-2α-dependent lymphangiogenic phenotype was confirmed in vivo using matrigel plug assays with supernatants of HIF-2α knockdown HepG2 cells. We identified and verified IGFBP1 as a HIF-2α target gene. The potential of HepG2 cells to induce lymphangiogenesis in two independent functional assays was significantly enhanced either by a knockdown of HIF-2α or by silencing IGFBP1. Moreover, we confirmed IGF as a potent pro-lymphatic growth factor with IGFBP1 being its negative modulator. We propose that HIF-2α acts as an important negative regulator of hepatic lymphangiogenesis in vitro and in vivo by inducing IGFBP1 and thus, interfering with IGF-signaling. Therefore, HIF-2α may constitute a critical target in HCC therapy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biology of the Cell 03/2015; 107(6). DOI:10.1111/boc.201400079 · 3.87 Impact Factor
  • Endoskopie heute 03/2015; 28(01). DOI:10.1055/s-0035-1545026 · 0.16 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Understanding of the physiological role of peroxisome proliferator-activated receptor gamma (PPARγ) offers new opportunities for the treatment of cancers, immune disorders and inflammatory diseases. In contrast to PPARγ agonists, few PPARγ antagonists have been studied, though they do exert immunomodulatory effects. Currently, no therapeutically useful PPARγ antagonist is commercially available. The aim of this study was to identify and kinetically characterise a new competitive PPARγ antagonist for therapeutic use. A PPARγ-dependent transactivation assay was used to kinetically characterise (E)-2-(5-((4-methoxy-2-(trifluoromethyl)quinolin-6-yl)methoxy)-2-((4-(trifluoromethyl)benzyl)oxy)-benzylidene)-hexanoic acid (MTTB) in kidney, T and monocytic cell lines. Cytotoxic effects were analysed and intracellular accumulation of MTTB was assessed by tandem mass spectrometry (LC-MS/MS). Potential interactions of MTTB with the PPARγ protein were suggested by molecular docking analysis. In contrast to non-competitive, irreversible inhibition caused by 2-chloro-5-nitrobenzanilide (GW9662), MTTB exhibited competitive antagonism against rosiglitazone in HEK293T and Jurkat T cells, with IC50 values in HEK293T cells of 4.3µM and 1.6µM, using the PPARγ ligand binding domain (PPARγ-LBD) and the full PPARγ protein, respectively. In all cell lines used, however, MTTB showed much higher intracellular accumulation than GW9662. MTTB alone exhibited weak partial agonistic effects and low cytotoxicity. Molecular docking of MTTB with the PPARγ-LBD supported direct interaction with the nuclear receptor. MTTB is a promising prototype for a new class of competitive PPARγ antagonists. It has weak partial agonistic and clear competitive antagonistic characteristics associated with rapid cellular uptake. Compared to commercially available PPARγ modulators, this offers the possibility of dose regulation of PPARγ and immune responses. Copyright © 2015 Elsevier B.V. All rights reserved.
    European Journal of Pharmacology 03/2015; 755. DOI:10.1016/j.ejphar.2015.02.034 · 2.68 Impact Factor
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: NF-E2-related factor 2 (Nrf2), known to protect against reactive oxygen species (ROS), recently emerged to resolve acute inflammatory responses in activated macrophages. Consequently, disruption of Nrf2 promotes a pro-inflammatory macrophage phenotype. In the current study, we addressed the impact of this macrophage phenotype on CD8+ T cell activation by using an antigen-driven co-culture model consistent of Nrf2-/- and Nrf2+/+ bone marrow derived macrophages (BMDMΦ) and transgenic OT-1 CD8+ T cells. OT-1 CD8+ T cells encode a T cell receptor that specifically recognizes MHCI-presented OVA(257-264) peptide, thereby causing a downstream T cell activation. Interestingly, co-culture of OVA(257-264)-pulsed Nrf2-/- BMDMΦ with transgenic OT-1 CD8+ T cells attenuated CD8+ T cell activation, proliferation, and cytotoxic function, compared to Nrf2+/+ BMDMΦ.Since the provision of low molecular thiols such as glutathione (GSH) or cysteine (Cys) by macrophages limits antigen-driven CD8+ T cell activation, we quantified the amount of intracellular and extracellular GSH and Cys in both co-cultures. Indeed, GSH levels were strongly decreased in Nrf2-/- co-cultures compared to wildtype counterparts. Supplementation of thiols in Nrf2-/- co-cultures via addition of glutathione ester, N-acetylcysteine, β-mercaptoethanol, or cysteine itself restored T cell proliferation as well as cytotoxicity by increasing intracellular GSH. Mechanistically, we identified two potential Nrf2-regulated genes involved in thiol synthesis in BMDMΦ: the cystine transporter subunit xCT and the modulatory subunit of the GSH synthesizing enzyme γ-GCS (GCLM). Pharmacological inhibition of γ-GCS-dependent GSH synthesis as well as knockdown of the cystine importer xCT in Nrf2+/+ BMDMΦ mimicked the effect of Nrf2-/- BMDMΦ on CD8+ T cell function. Our findings demonstrate, that reduced levels of GCLM as well as xCT in Nrf2-/- BMDMΦ limit GSH availability, thereby inhibiting antigen-induced CD8+ T cell function.
    Free Radical Biology and Medicine 02/2015; 83. DOI:10.1016/j.freeradbiomed.2015.02.004 · 5.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Extracorporeal photopheresis (ECP) is a widely used clinical cell-based therapy exhibiting efficacy in heterogenous immune-mediated diseases such as cutaneous T cell lymphoma, graft-versus-host disease, and organ allograft rejection. Despite its documented efficacy in cancer immunotherapy, little is known regarding the induction of immunostimulatory mediators by ECP. In this article, we show that ECP promotes marked release of the prototypic immunostimulatory cytokine IL-1β. ECP primes IL-1β production and activates IL-1β maturation and release in the context of caspase-1 activation in monocytes and myeloid dendritic cells. Of interest, IL-1β maturation by ECP was fully intact in murine cells deficient in caspase-1, suggesting the predominance of an inflammasome-independent pathway for ECP-dependent IL-1β maturation. Clinically, patient analysis revealed significantly increased IL-1β production in stimulated leukapheresis concentrates and peripheral blood samples after ECP. Collectively, these results provide evidence for promotion of IL-1β production by ECP and offer new insight into the immunostimulatory capacity of ECP. Copyright © 2015 by The American Association of Immunologists, Inc.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract The sphingolipid sphingosine-1-phosphate (S1P) has various functions in immune cell biology, regulating survival, proliferation, and, most prominently, migration. S1P couples to five G protein-coupled receptors (S1PR1-5) to transduce its effects on immune cell function. Expression of S1PR4 is restricted to immune cells. However, its impact on immune cell biology is largely elusive. In the current study, we intended to answer the question whether S1P might affect plasmacytoid dendritic cell (pDC) migration, which dominantly express S1PR4. pDC are highly specialized cells producing large amounts of type I interferon in response to TLR7/9 ligands after viral infection or during autoimmunity. Surprisingly, we noticed a reduced abundance of pDC, particularly CD4- pDC, in all organs of S1PR4-deficient versus wildtype mice. This effect was not due to altered migration of mature pDC, but rather due to a reduced potential of pDC progenitors, especially common DC progenitors, to differentiate into pDCs. In vitro studies suggested that reduced S1PR4-deficient pDC progenitor differentiation into mature pDC might be explained by both migration and differentiation of pDC progenitors in the bone marrow. Since S1PR4 also affected the differentiation of CD34+ human hematopoietic stem cells into pDC, interfering with S1PR4 might be useful to reduce pDC numbers during autoimmunity.
    Biological Chemistry 01/2015; 396(6-7). DOI:10.1515/hsz-2014-0271 · 2.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Sepsis still emerges as a major cause of patient death in intensive care units. Therefore, new therapeutic approaches are mandatory. Because during sepsis progression cytotoxic T lymphocytes (CTLs) can be activated in an autoimmune fashion contributing to multiorgan damage, it remains unclear whether CTLs are activated toward alloantigenic cells. This is important for patients receiving an immunosuppressive therapy to permit organ transplantation and, thus, known to be at high risk for developing sepsis. Therefore, we analyzed whether sepsis activates CTL toward alloantigenic target cells and whether this can be inhibited by PPARγ activation, known to block T helper cell responses. To mimic septic conditions, CTLs were isolated from cecal ligation and puncture-operated mice. CTL cytotoxicity was analyzed following a direct alloantigenic activation regime or following classical ex vivo splenocyte-driven activation in a cytotoxicity assay. With this readout, we found that CTL derived from septic mice enhanced cytotoxicity toward alloantigenic target cells, which was lowered by in vivo and ex vivo PPARγ activation. With CTL derived from T cell-specific PPARγ knockout mice, PPARγ activation was ineffective, pointing to a PPARγ-dependent mechanism. In vivo and ex vivo PPARγ activation reduced Fas and granzyme B expression in activated CTL. Key message In the sepsis CLP mouse model, CTLs are activated toward alloantigenic target cells. Sepsis-mediated alloantigenic CTL activation is blocked in vivo by PPARγ activation. PPARγ deletion or antagonization restored rosiglitazone-dependent inhibition of CTL cytotoxicity. PPARγ inhibits the expression of Fas and granzyme B in CTLs.
    Journal of Molecular Medicine 01/2015; 93(6). DOI:10.1007/s00109-014-1249-8 · 4.74 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hypoxia promotes progression of hepatocellular carcinoma (HCC), not only affecting tumor cell proliferation and invasion, but also angiogenesis and thus, increasing the risk of metastasis. Hypoxia inducible factors (HIF)-1α and -2α cause adaptation of tumors to hypoxia, still with uncertainties towards the angiogenic switch. We created a stable knockdown of HIF-1α and HIF-2α in HepG2 cells and generated cocultures of HepG2 spheroids with embryonic bodies as an in vitro tumor model mimicking the cancer microenvironment. The naturally occuring oxygen and nutrient gradients within the cocultures allow us to question the role of distinct HIF isoforms in regulating HCC angiogenesis. In cocultures with a HIF-2α knockdown, angiogenesis was attenuated, while the knockdown of HIF-1α was without effect. Microarray analysis identified plasminogen activator inhibitor 1 (PAI-1) as a HIF-2α target gene in HepG2 cells. The knockdown of PAI-1 in HepG2 cells also lowered angiogenesis. Blocking plasmin, the downstream target of PAI-1, with aprotinin in HIF-2α knockdown (k/d) cells proved a cause-effect relation and restored angiogenesis, with no effect on control cocultures. Suggestively, HIF-2α increases PAI-1 to lower concentrations of active plasmin, thereby supporting angiogenesis. We conclude that the HIF-2α target gene PAI-1 favors the angiogenic switch in HCC. Copyright © 2014. Published by Elsevier Inc.
    Experimental Cell Research 12/2014; 331(1). DOI:10.1016/j.yexcr.2014.11.018 · 3.37 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Macrophages play important roles in many diseases and are frequently found in hypoxic areas. A chronic hypoxic microenvironment alters global cellular protein expression but molecular details remain poorly understood. Although hypoxia inducible factor (HIF) is an established transcription factor allowing adaption to acute hypoxia, responses to chronic hypoxia are more complex. Based on a two-dimensional differential gel electrophoresis (2D-DIGE) approach, we aimed to identify proteins that are exclusively expressed under chronic but not acute hypoxia (1% O2). One of the identified proteins was cathepsin B (CTSB) and a knockdown of either HIF-1α or -2α in primary human macrophages pointed to a HIF-2α-dependency. Although ChIP experiments confirmed HIF-2 binding to a CTSB enhancer in acute hypoxia, an increase of CTSB mRNA was only evident under chronic hypoxia. Along those lines, CTSB mRNA stability increased at 48 h but not at 8 h of hypoxia. However, RNA stability at 8 h hypoxia was enhanced by a knockdown of tristetraprolin (TTP). Inactivation of TTP under prolonged hypoxia was facilitated by c-jun N-terminal kinase (JNK) and inhibition of this kinase lowered CTSB mRNA levels and stability. We postulate a TTP-dependent mechanism to explain delayed expression of CTSB under chronic hypoxia. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
    Molecular and Cellular Biology 12/2014; 35(3). DOI:10.1128/MCB.01034-14 · 5.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Macrophages (MΦ) often accumulate in hypoxic areas, where they significantly influence disease progression. Anti-inflammatory cytokines, such as IL-10, generate alternatively activated macrophages that support tumor growth. To understand how alternative activation affects the transcriptional profile of hypoxic macrophages, we globally mapped binding sites of hypoxia-inducible factor (HIF)-1α and HIF-2α in primary human monocyte-derived macrophages prestimulated with IL-10. 713 HIF-1 and 795 HIF-2 binding sites were identified under hypoxia. Pretreatment with IL-10 altered the binding pattern, with 120 new HIF-1 and 188 new HIF-2 binding sites emerging. HIF-1 binding was most prominent in promoters, while HIF-2 binding was more abundant in enhancer regions. Comparison of ChIP-seq data obtained in other cells revealed a highly cell type specific binding of HIF. In MΦ HIF binding occurred preferentially in already active enhancers or promoters. To assess the roles of HIF on gene expression, primary human macrophages were treated with siRNA against HIF-1α or HIF-2α, followed by genome-wide gene expression analysis. Comparing mRNA expression to the HIF binding profile revealed a significant enrichment of hypoxia-inducible genes previously identified by ChIP-seq. Analysis of gene expression under hypoxia alone and hypoxia/IL-10 showed the enhanced induction of a set of genes including PLOD2 and SLC2A3, while another group including KDM3A and ADM remained unaffected or was reduced by IL-10. Taken together IL-10 influences the DNA binding pattern of HIF and the level of gene induction. Copyright © 2014. Published by Elsevier B.V.
    Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 11/2014; 1849(1):10-22. DOI:10.1016/j.bbagrm.2014.10.006 · 5.44 Impact Factor
  • Michaela Jung, Christina Mertens, Bernhard Brüne
    [Show abstract] [Hide abstract]
    ABSTRACT: Macrophages are central in regulating iron homeostasis, which is tightly linked to their versatile role during innate immunity. They sequester iron by phagocytosis of senescent erythrocytes and represent a major source of available iron in the body. Macrophage iron homeostasis is coupled to the functional heterogeneity and plasticity of these cells, with their extreme roles during inflammation, immune modulation, and resolution of inflammation. It is now appreciated that the macrophage polarization process dictates expression profiles of genes involved in iron metabolism. Therefore, macrophages have evolved a multitude of mechanisms to sequester, transport, store, and release iron. A new, enigmatic protein entering the iron scene and affecting the macrophage phenotype is lipocalin-2. Iron sequestration in macrophages depletes the microenvironment, thereby limiting extracellular pathogen or tumor growth, while fostering inflammation. In contrast, iron release from macrophages contributes to bystander cell proliferation, which is important for tissue regeneration and repair. This dichotomy is also reflected by the dual role of lipocalin-2 in macrophages. Unfortunately, the iron release macrophage phenotype is also a characteristic of tumor associated macrophages and stimulates tumor cell survival and growth. Iron sequestration versus its release is now appreciated to be associated with the macrophage polarization program and can be used to explain a number of biological functions attributed to distinct macrophage phenotypes. Here we discuss macrophage iron homeostasis with a special focus on lipocalin-2 related to the formation and function of tumor associated macrophages.
    Immunobiology 09/2014; 220(2). DOI:10.1016/j.imbio.2014.09.011 · 3.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Lipoxins belong to the family of so-called pro-resolving endogenous lipid mediators which are derived from arachidonic acid and play a key role in the counter-regulation of inflammation. Arachidonic acid is also precursor of multiple pro-inflammatory lipid mediators, such as prostaglandins and leukotrienes, which are simultaneously present in biological compartments. The close structural relationship between several of these lipid mediators and the absence of blank matrix samples enormously complicates the unequivocal identification of these compounds. The determination of lipoxin A4 has been accomplished by chromatographic separation using a C18 reversed phase column and tandem mass spectrometry detection. Samples were liquid-liquid extracted with ethyl acetate before injection. Identification of the analyte was done based on three criteria: retention time, ratio of the m/z transitions and MS/MS spectrum. To avoid false positive results due to endogenous interferences, the extracted samples were re-injected into a chiral Lux Amylose-2 chromatographic column. The authors recommend the use of chiral chromatography in the determination of pro-resolving lipid mediators, together with transition area ratio and fragmentation spectra to improve selectivity for identification and quantitation purposes.
    Talanta 09/2014; 127:82–87. DOI:10.1016/j.talanta.2014.03.051 · 3.51 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Lipopolysaccharide (LPS)-induced activation of TLR4 (toll-like receptor 4) is followed by a subsequent overwhelming inflammatory response, a hallmark of the first phase of sepsis. Therefore, counteracting excessive innate immunity by autophagy is important to contribute to the termination of inflammation. However, the exact molecular details of this interplay are only poorly understood. Here, we show that PELI3/Pellino3 (pellino E3 ubiquitin protein ligase family member 3), which is an E3 ubiquitin ligase and scaffold protein in TLR4-signaling, is impacted by autophagy in macrophages (MΦ) after LPS stimulation. We noticed an attenuated mRNA expression of proinflammatory Il1b (interleukin 1, β) in Peli3 knockdown murine MΦ in response to LPS treatment. The autophagy adaptor protein SQSTM1/p62 (sequestosome 1) emerged as a potential PELI3 binding partner in TLR4-signaling. siRNA targeting Sqstm1 and Atg7 (autophagy related 7), pharmacological inhibition of autophagy by wortmannin as well as blocking the lysosomal vacuolar-type H(+)-ATPase by bafilomycin A 1 augmented PELI3 protein levels, while inhibition of the proteasome had no effect. Consistently, treatment to induce autophagy by MTOR (mechanistic target of rapamycin (serine/threonine kinase)) inhibition or starvation enhanced PELI3 degradation and reduced proinflammatory Il1b expression. PELI3 was found to be ubiquitinated upon LPS stimulation and point mutation of PELI3-lysine residue 316 (Lys316Arg) attenuated Torin2-dependent degradation of PELI3. Immunofluorescence analysis revealed that PELI3 colocalized with the typical autophagy markers MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β) and LAMP2 (lysosomal-associated membrane protein 2). Our observations suggest that autophagy causes PELI3 degradation during TLR4-signaling, thereby impairing the hyperinflammatory phase during sepsis.
    Autophagy 08/2014; 10(11). DOI:10.4161/auto.32178 · 11.42 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Emerging lines of evidence indicate that production of reactive oxygen species (ROS) at distinct sites of the nociceptive system contributes to the processing of neuropathic pain. However, the mechanisms underlying ROS production during neuropathic pain processing are not fully understood. We here detected the ROS-generating NADPH oxidase isoform Nox2 in macrophages of dorsal root ganglia (DRGs) in mice. In response to peripheral nerve injury, Nox2-positive macrophages were recruited to DRGs, and ROS production was increased in a Nox2-dependent manner. Nox2-deficient mice displayed reduced neuropathic pain behavior after peripheral nerve injury, whereas their immediate responses to noxious stimuli were normal. Moreover, injury-induced upregulation of tumor necrosis factor α was absent and ATF3-induction was reduced in DRGs of Nox2-deficient mice suggesting an attenuated macrophage-neuron signaling. These data suggest that Nox2-dependent ROS production in macrophages recruited to DRGs contributes to neuropathic pain hypersensitivity, underlining the observation that Nox-derived ROS exert specific functions during the processing of pain.
    Pain 08/2014; 155(10). DOI:10.1016/j.pain.2014.08.013 · 5.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: -Vitamin D deficiency in humans is frequent and has been associated with inflammation. The role of the active hormone, 1,25-dihydroxy-vitamin D3 (1,25-VitD3) in the cardiovascular system is controversial. High doses induce vascular calcification; vitamin D3 deficiency, however, has been linked to cardiovascular disease as the hormone has anti-inflammatory properties. We therefore hypothesized that 1,25-VitD3 promotes regeneration after vascular injury.
    Circulation 07/2014; 130(12). DOI:10.1161/CIRCULATIONAHA.114.010650 · 14.95 Impact Factor
  • Dmitry Namgaladze, Bernhard Brüne
    [Show abstract] [Hide abstract]
    ABSTRACT: Macrophage polarization elicits various metabolic alterations which in turn influence the polarized phenotype. Activation of glycolytic metabolism accompanies and supports macrophage pro-inflammatory M1 polarization. In contrast, M2 polarization of murine macrophages in response to the Th2 cytokine interleukin-4 (IL-4) was linked to the up-regulation of mitochondrial oxidative metabolism and fatty acid oxidation (FAO), which was necessary for coining an IL-4-polarized phenotype. Here we investigated whether similar mechanisms operate in human macrophages stimulated with IL-4. IL-4 causes only moderate changes of mitochondrial oxidative metabolism and FAO, correlating with an unaltered expression of peroxisome proliferator-activated receptor-γ coactivator 1 α/β (PGC-1α/β), the master transcriptional regulators of mitochondrial biogenesis. Furthermore, attenuating FAO had no effect on IL-4-induced polarization-associated gene expression. Apparently, FAO is dispensable for IL-4-induced polarization of human macrophages, pointing to fundamental differences in the metabolic requirements of macrophage phenotype alterations between mice and humans.
    Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 06/2014; 1841(9). DOI:10.1016/j.bbalip.2014.06.007 · 4.50 Impact Factor

Publication Stats

10k Citations
1,326.92 Total Impact Points


  • 2005–2015
    • Goethe-Universität Frankfurt am Main
      • • Institute of Biochemistry
      • • Institut für Biochemie I - Pathobiochemie
      Frankfurt, Hesse, Germany
    • University of Adelaide
      Tarndarnya, South Australia, Australia
  • 2005–2013
    • University Hospital Frankfurt
      Frankfurt, Hesse, Germany
  • 2007
    • Academy of Athens
      Athínai, Attica, Greece
  • 2001–2005
    • Technische Universität Kaiserslautern
      • Division of Cell Biology
      Kaiserlautern, Rheinland-Pfalz, Germany
  • 2003
    • Universität zu Lübeck
      • Institut für Physiologie
      Lübeck, Schleswig-Holstein, Germany
  • 2002
    • Sapienza University of Rome
      Roma, Latium, Italy
  • 1995–2001
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      • Faculty of Medicine
      Erlangen, Bavaria, Germany
  • 1997–2000
    • Universitätsklinikum Erlangen
      Erlangen, Bavaria, Germany
  • 1999
    • Case Western Reserve University
      Cleveland, Ohio, United States
  • 1996
    • National Public Health Institute
      Helsinki, Southern Finland Province, Finland
  • 1987–1996
    • Universität Konstanz
      • Molecular Toxicology
      Constance, Baden-Württemberg, Germany
  • 1993
    • Research Triangle Park Laboratories, Inc.
      Raleigh, North Carolina, United States