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Dive into the research topics where Andreas Weigert is active.

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Featured researches published by Andreas Weigert.


Antioxidants & Redox Signaling | 2013

Redox Control of Inflammation in Macrophages

Bernhard Brüne; Nathalie Dehne; Nina Grossmann; Michaela Jung; Dmitry Namgaladze; Tobias Schmid; Andreas von Knethen; Andreas Weigert

Macrophages are present throughout the human body, constitute important immune effector cells, and have variable roles in a great number of pathological, but also physiological, settings. It is apparent that macrophages need to adjust their activation profile toward a steadily changing environment that requires altering their phenotype, a process known as macrophage polarization. Formation of reactive oxygen species (ROS), derived from NADPH-oxidases, mitochondria, or NO-producing enzymes, are not necessarily toxic, but rather compose a network signaling system, known as redox regulation. Formation of redox signals in classically versus alternatively activated macrophages, their action and interaction at the level of key targets, and the resulting physiology still are insufficiently understood. We review the identity, source, and biological activities of ROS produced during macrophage activation, and discuss how they shape the key transcriptional responses evoked by hypoxia-inducible transcription factors, nuclear-erythroid 2-p45-related factor 2 (Nrf2), and peroxisome proliferator-activated receptor-γ. We summarize the mechanisms how redox signals add to the process of macrophage polarization and reprogramming, how this is controlled by the interaction of macrophages with their environment, and addresses the outcome of the polarization process in health and disease. Future studies need to tackle the option whether we can use the knowledge of redox biology in macrophages to shape their mediator profile in pathophysiology, to accelerate healing in injured tissue, to fight the invading pathogens, or to eliminate settings of altered self in tumors.


Nitric Oxide | 2008

Nitric oxide, apoptosis and macrophage polarization during tumor progression.

Andreas Weigert; Bernhard Brüne

Decreased oxygen availability evokes adaptive responses, which are primarily under the gene regulatory control of hypoxia inducible factor-1 (HIF-1). Hypoxic cores of a growing tumor cell mass use this signaling circuit to gain access to further blood and nutrient supply that guarantees their continuing growth. Interestingly, NO shares with hypoxia the ability to block prolyl-hydroxylase (PHD) activity, and thus the ability to stabilize hypoxia inducible factor 1 alpha (HIF-1 alpha). Under these conditions NO mimics hypoxia, which might contribute to tumor development. Stimulating/triggering innate immune responses associated with macrophage activation often correlated with iNOS induction and massive NO release, which is known to kill NO-sensitive tumors. However, this safeguard mechanism will only be effective if all tumor cells are eliminated because apoptotic death of tumor cells implies mechanisms to stop macrophages from attacking the survivors. Apoptotic cells release factors, among others sphingosine-1-phosphate (S1P), which reprogram macrophages. Macrophage reprogramming shifts responses from a M1 and thus pro-inflammatory and killing phenotype, to a M2 phenotype, which is anti-inflammatory and pro-angiogenic. These polarized tumor associated macrophages (TAM) are actively contributing to tumor development. Apparently NO uses distinct signaling pathways that could serve as an explanation to understand how NO affects tumor development. Some of these pathways, especially the ability of NO to mimic hypoxia at the level of HIF-1 alpha, as well as the role of macrophage polarization by apoptotic cells with accompanying changes in the iNOS versus arginase ratio and activities, will be discussed to better understand how NO affects tumor growth.


Molecular Biology of the Cell | 2009

Heme oxygenase-1 contributes to an alternative macrophage activation profile induced by apoptotic cell supernatants.

Nicole Weis; Andreas Weigert; Andreas von Knethen; Bernhard Brüne

Apoptotic cells (AC) are rapidly engulfed by professional phagocytes such as macrophages to avoid secondary necrosis and thus inflammation. Recognition of AC polarizes macrophages toward an anti-inflammatory phenotype, which shows homology to an alternatively activated M2 macrophage. However, mechanistic details provoking these phenotype alterations are incompletely understood. Here, we demonstrate a biphasic up-regulation of heme oxygenase-1 (HO-1), a protein that bears an antiapoptotic as well as an anti-inflammatory potential, in primary human macrophages, which were exposed to the supernatant of AC. Although the first phase of HO-1 induction at 6 h was accomplished by AC-derived sphingosine-1-phosphate (S1P) acting via S1P receptor 1, the second wave of HO-1 induction at 24 h was attributed to autocrine signaling of vascular endothelial growth factor A (VEGFA), whose expression and release were facilitated by S1P. Whereas VEGFA release from macrophages was signal transducer and activator of transcription (STAT) 1-dependent, vascular endothelial growth factor itself triggered STAT1/STAT3 heterodimer formation, which bound to and activated the HO-1 promoter. Knockdown of HO-1 proved its relevance in facilitating enhanced expression of the antiapoptotic proteins Bcl-2 and Bcl-X(L), as well as the anti-inflammatory adenosine receptor A(2A). These findings suggest that HO-1, which is induced by AC-derived S1P, is critically involved in macrophage polarization toward an M2 phenotype.


Carcinogenesis | 2010

Knockout of HIF-1α in tumor-associated macrophages enhances M2 polarization and attenuates their pro-angiogenic responses

Christian Werno; Heidi Menrad; Andreas Weigert; Nathalie Dehne; Sergij Goerdt; Kai Schledzewski; Julia Kzhyshkowska; Bernhard Brüne

Tumor-associated macrophages (TAMs) constitute major infiltrates of solid tumors and express a marker profile that characterizes alternatively activated macrophages (MФs). TAMs accumulate in hypoxic tumor regions, express high amounts of hypoxia-inducible factor-1 (HIF-1) and contribute to tumor angiogenesis and invasiveness. However, the precise role of HIF-1 on MФ infiltration and phenotype alterations remains poorly defined. Therefore, we cocultured wild type (wt) versus HIF-1α(-/-) MФs with tumor spheroids. Both, wt and HIF-1α(-/-) MФs, infiltrated hypoxic regions of tumor spheroids at equal rates and got alternatively activated. Interestingly, significantly higher amounts of HIF-1α(-/-) MФs expressed the TAM markers CD206 and stabilin-1 compared with wt phagocytes. Stimulation of infiltrated TAMs with lipopolysaccharide (LPS)/interferon-γ revealed a reduced expression of the pro-inflammatory markers interleukin (IL)-6, tumor necrosis factor-α and inducible nitric oxide synthase in HIF-1α(-/-) MФs. Furthermore, HIF-1α(-/-) MФs were less cytotoxic toward tumor cells. Although infiltration of MФs increased the invasive potential of tumor spheroids independently of HIF-1, the ability to stimulate differentiation of stem cells toward CD31-positive cells was triggered by wt but not by HIF-1α(-/-) MФs. Our data suggest that HIF-1α-deficient MФs develop a more prominent TAM marker profile accompanied by reduced cytotoxicity, whereas HIF-1 seems indispensable for the angiogenesis-promoting properties of TAMs.


Molecular Cancer Research | 2009

Hypoxia enhances sphingosine kinase 2 activity and provokes sphingosine-1-phosphate-mediated chemoresistance in A549 lung cancer cells.

Steffen E. Schnitzer; Andreas Weigert; Jie Zhou; Bernhard Brüne

Hypoxia and signaling via hypoxia-inducible factor-1 (HIF-1) is a key feature of solid tumors and is related to tumor progression as well as treatment failure. Although it is generally accepted that HIF-1 provokes tumor cell survival and induces chemoresistance under hypoxia, HIF-1-independent mechanisms operate as well. We present evidence that conditioned medium obtained from A549 cells, incubated for 24 h under hypoxia, protected naive A549 cells from etoposide-induced cell death. Lipid extracts generated from hypoxia-conditioned medium still rescued cells from apoptosis induced by etoposide. Specifically, the bioactive lipid sphingosine-1-phosphate (S1P) not only was essential for cell viability of A549 cells but also protected cells from apoptosis. We noticed an increase in sphingosine kinase 2 (SphK2) protein level and enzymatic activity under hypoxia, which correlated with the release of S1P into the medium. Knockdown of SphK2 using specific small interfering RNA relieved chemoresistance of A549 cells under hypoxia and conditioned medium obtained from SphK2 knockdown cells was only partially protective. Coincubations of conditioned medium with VPC23019, a S1P1/S1P3 antagonist, reduced protection of conditioned medium, with the further notion that p42/44 mitogen-activated protein kinase transmits autocrine or paracrine survival signaling downstream of S1P1/S1P3 receptors. Our data suggest that hypoxia activates SphK2 to promote the synthesis and release of S1P, which in turn binds to S1P1/S1P3 receptors, thus activating p42/44 mitogen-activated protein kinase to convey autocrine or paracrine protection of A549 cells. (Mol Cancer Res 2009;7(3):393–401)


International Journal of Cancer | 2009

Sphingosine kinase 2 deficient tumor xenografts show impaired growth and fail to polarize macrophages towards an anti-inflammatory phenotype

Andreas Weigert; Susanne Schiffmann; Divya Sekar; Stephanie Ley; Heidi Menrad; Christian Werno; Sabine Grösch; Gerd Geisslinger; Bernhard Brüne

A challenging task of the immune system is to fight cancer cells. However, a variety of human cancers educate immune cells to become tumor supportive. This is exemplified for tumor‐associated macrophages (TAMs), which are polarized towards an anti‐inflammatory and cancer promoting phenotype. Mechanistic explanations, how cancer cells influence the macrophage phenotype are urgently needed to address potential anti‐cancer strategies along this line. One potential immune modulating compound, sphingosine‐1‐phosphate (S1P), was recently highlighted in both tumor growth and immune modulation. Using a xenograft model in nude mice, we demonstrate a supportive role of sphingosine kinase 2 (SphK2), one of the S1P‐producing enzymes for tumor progression. The growth of SphK2‐deficient MCF‐7 breast tumor xenografts was markedly delayed when compared with controls. Infiltration of macrophages in SphK2‐deficient and control tumors was comparable. However, TAMs from SphK2‐deficient tumors displayed a pronounced anti‐tumor phenotype, showing an increased expression of pro‐inflammatory markers/mediators such as NO, TNF‐α, IL‐12 and MHCII and a low expression of anti‐inflammatory IL‐10 and CD206. These data suggest a role for S1P, generated by SphK2, in early tumor development by affecting macrophage polarization.


Immunobiology | 2009

Regulation of macrophage function by sphingosine-1-phosphate.

Andreas Weigert; Nicole Weis; Bernhard Brüne

The bioactive lipid sphingosine-1-phosphate (S1P) fulfils manifold tasks in the immune system acting in auto- and/or paracrine fashion. This includes regulation of apoptosis, migration and proliferation. Upon its generation by sphingosine kinases from plasma membrane sphingolipids, S1P can either act as a second messenger within cells or can be released from cells to occupy a family of specific G-protein-coupled receptors (S1P1-5). This diversity is reflected by the impact of S1P on macrophage biology and function. Over the last years it became apparent that the sphingosine kinase/S1P/S1P-receptor signalling axis in macrophages might play a central role in the pathogenesis of inflammatory diseases such as atherosclerosis, asthma, rheumatoid arthritis and cancer. Here, we summarize the current knowledge of the function of S1P in macrophage biology and discuss potential implications for pathology.


The FASEB Journal | 2007

Apoptotic cells induce arginase II in macrophages, thereby attenuating NO production

Axel M. Johann; Vera Barra; Anne-Marie Kuhn; Andreas Weigert; Andreas von Knethen; Bernhard Brüne

In recent years it has become apparent that removal of apoptotic cells (AC) by professional phagocytes alters the macrophage phenotype. This change is characterized by attenuated proinflammatory cytokine expression and NO production, which mechanistically remained unexplained. With the intention to explore molecular mechanisms underlying reduced NO formation, we showed that NO production in IFNγ‐stimulated murine RAW264.7 macrophages exposed to AC but not to either necrotic or viable human Jurkat cells was significantly reduced although iNOS expression remained high compared with controls. Analyzing iNOS activity in the cell extracts by using the radioactive L‐arginine/citrulline conversion assay revealed increased ornithine production over citrulline in cells exposed to AC. RT‐PCR, Western blot, and luciferase reporter analysis supported the idea of an arginase II increase in response to AC. The involvement of argi‐nase in modulating NO formation in response to AC was substantiated by the arginase inhibitor N“‐hydroxy‐nor‐L‐arginine. Moreover, knockdown of arginase II by siRNA allowed recovery of NO production. Experiments with AC‐conditioned medium demonstrated that a soluble lipid factor, rather than phagocytosis of AC, modulated NO production in macrophages. We conclude that AC release a lipid factor to modulate NO formation in macrophages via arginase II up‐regulation, thereby contributing to innate immune regulation.—Johann, A. M., Barra, V., Kuhn, A‐M., Weigert, A., von Knethen, A., Brune, B. Apoptotic cells induce arginase II in macrophages, thereby attenuating NO production. FASEB J. 21, 2704–2712 (2007)


Journal of Immunology | 2008

Apoptotic Cell-Derived Sphingosine-1-Phosphate Promotes HuR-Dependent Cyclooxygenase-2 mRNA Stabilization and Protein Expression

Axel M. Johann; Andreas Weigert; Wolfgang Eberhardt; Anne-Marie Kuhn; Vera Barra; Andreas von Knethen; Josef Pfeilschifter; Bernhard Brüne

Removal of apoptotic cells by phagocytes is considered a pivotal immune regulatory process. Although considerable knowledge has been obtained on the postphagocytic macrophage phenotype, there is little information on molecular mechanisms, which provoke macrophage polarization. In this study, we show that human apoptotic Jurkat cells (AC) or AC-conditioned medium (CM) rapidly induces cyclooxygenase-2 (COX-2) expression in mouse RAW264.7 macrophages via sphingosine-1-phosphate (S1P). Pharmacological inhibition of S1P release from AC or using CM from cells with a knockdown of sphingosine kinase 2 in human MCF-7 cells abrogates this effect. Expression of COX-2 resulted from an increase in mRNA stability via its 3′-untranslated region (UTR), shown by COX-2–3′-UTR and AU-rich element-driven reporter assays. Western analysis corroborated increased nucleocytoplasmic shuttling of the RNA-binding protein HuR after CM treatment. RNA EMSA analysis revealed an S1P- and CM-mediated increase in HuR-RNA binding to a COX-2-specific UTR, whereas HuR knockdown pointed to its importance for S1P in CM-induced COX-2 expression. Immunofluorescence microscopy of phospholipase A2 (PLA2) and ELISA analysis of PGE2 revealed activation of PLA2 and production of PGE2 in response to CM but not S1P. S1P, released from AC, uses HuR to stabilize COX-2 mRNA and thus to increase COX-2 protein expression. However, only CM also activates PLA2 to provide the substrate for COX-2. Our data underscore the importance of S1P in AC-mediated immune regulation, by stabilizing COX-2 mRNA in macrophages, a prerequisite for PGE2 formation.


Journal of Biological Chemistry | 2011

Anti-inflammatory Role of Microsomal Prostaglandin E Synthase-1 in a Model of Neuroinflammation

Christian Brenneis; Ovidiu Coste; Kai Altenrath; Carlo Angioni; Helmut Schmidt; Claus-Dieter Schuh; Dong Dong Zhang; Marina Henke; Andreas Weigert; Bernhard Brüne; Barry B. Rubin; Rolf M. Nüsing; Klaus Scholich; Gerd Geisslinger

A major immunological response during neuroinflammation is the activation of microglia, which subsequently release proinflammatory mediators such as prostaglandin E2 (PGE2). Besides its proinflammatory properties, cyclooxygenase-2 (COX-2)-derived PGE2 has been shown to exhibit anti-inflammatory effects on innate immune responses. Here, we investigated the role of microsomal PGE2 synthase-1 (mPGES-1), which is functionally coupled to COX-2, in immune responses using a model of lipopolysaccharide (LPS)-induced spinal neuroinflammation. Interestingly, we found that activation of E-prostanoid (EP)2 and EP4 receptors, but not EP1, EP3, PGI2 receptor (IP), thromboxane A2 receptor (TP), PGD2 receptor (DP), and PGF2 receptor (FP), efficiently blocked LPS-induced tumor necrosis factor α (TNFα) synthesis and COX-2 and mPGES-1 induction as well as prostaglandin synthesis in spinal cultures. In vivo, spinal EP2 receptors were up-regulated in microglia in response to intrathecally injected LPS. Accordingly, LPS priming reduced spinal synthesis of TNFα, interleukin 1β (IL-1β), and prostaglandins in response to a second intrathecal LPS injection. Importantly, this reduction was only seen in wild-type but not in mPGES-1-deficient mice. Furthermore, intrathecal application of EP2 and EP4 agonists as well as genetic deletion of EP2 significantly reduced spinal TNFα and IL-1β synthesis in mPGES-1 knock-out mice after LPS priming. These data suggest that initial inflammation prepares the spinal cord for a negative feedback regulation by mPGES-1-derived PGE2 followed by EP2 activation, which limits the synthesis of inflammatory mediators during chronic inflammation. Thus, our data suggest a role of mPGES-1-derived PGE2 in resolution of neuroinflammation.

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Bernhard Brüne

Goethe University Frankfurt

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Gerd Geisslinger

Goethe University Frankfurt

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Javier Mora

Goethe University Frankfurt

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Nathalie Dehne

Goethe University Frankfurt

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Michaela Jung

Goethe University Frankfurt

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Ralf P. Brandes

Goethe University Frankfurt

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Tobias Schmid

Goethe University Frankfurt

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Dmitry Namgaladze

Goethe University Frankfurt

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Klaus Scholich

Goethe University Frankfurt

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