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Future Oncology 01/2013; 9(1):1-4. · 3.16 Impact Factor
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Gitta M Seleznik,
Theresia Reding,
Franziska Romrig,
Yasuyuki Saito,
Alexander Mildner,
Stephan Segerer,
Li-Kang Sun,
Stephan Regenass,
Maciej Lech,
Hans-Joachim Anders, [......],
Andrew Macpherson,
Markus G Manz,
Achim Weber,
Jeffrey L Browning,
Melek Canan Arkan,
Thomas Rülicke,
Adriano Aguzzi,
Marco Prinz,
Rolf Graf, Mathias Heikenwalder
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ABSTRACT: Little is known about the pathogenic mechanisms of autoimmune pancreatitis (AIP), an increasingly recognized, immune-mediated form of chronic pancreatitis. Current treatment options are limited and disease relapse is frequent. We investigated factors that contribute to the development of AIP and new therapeutic strategies.
We used quantitative polymerase chain reaction, immunohistochemical, and enzyme-linked immunosorbent analyses to measure the expression of cytokines and chemokines in tissue and serum samples from patients with and without AIP. We created a mouse model of human AIP by overexpressing lymphotoxin (LT)α and β specifically in acinar cells (Ela1-LTab mice).
Messenger RNA levels of LTα and β were increased in pancreatic tissues from patients with AIP, compared with controls, and expression of chemokines (CXCL13, CCL19, CCL21, CCL1, and B-cell-activating factor) was increased in pancreatic and serum samples from patients. Up-regulation of these factors was not affected by corticosteroid treatment. Acinar-specific overexpression of LTαβ (Ela1-LTαβ) in mice led to an autoimmune disorder with various features of AIP. Chronic inflammation developed only in the pancreas but was sufficient to cause systemic autoimmunity. Acinar-specific overexpression of LTαβ did not cause autoimmunity in mice without lymphocytes (Ela1-LTab/Rag1(-/-)); moreover, lack of proinflammatory monocytes (Ela1-LTab/Ccr2(-/-)) failed to prevent AIP but prevented early pancreatic tissue damage. Administration of corticosteroids reduced pancreatitis but did not affect production of autoantibodies, such as antipancreatic secretory trypsin inhibitor in Ela1-LTab mice. In contrast, inhibition of LTβR signaling reduced chemokine expression, renal immune-complex deposition, and features of AIP in Ela1-LTab mice.
Overexpression of LTαβ specifically in acinar cells of mice causes features of AIP. Reagents that neutralize LTβR ligands might be used to treat patients with AIP.
Gastroenterology 08/2012; 143(5):1361-74. · 11.68 Impact Factor
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ABSTRACT: Neuroinvasion and subsequent destruction of the central nervous system by prions are typically preceded by a colonization phase in lymphoid organs. An important compartment harboring prions in lymphoid tissue is the follicular dendritic cell (FDC), which requires both tumor necrosis factor receptor 1 (TNFR1) and lymphotoxin β receptor (LTβR) signaling for maintenance. However, prions are still detected in TNFR1⁻/⁻ lymph nodes despite the absence of mature FDCs. Here we show that TNFR1-independent prion accumulation in lymph nodes depends on LTβR signaling. Loss of LTβR signaling, but not of TNFR1, was concurrent with the dedifferentiation of high endothelial venules (HEVs) required for lymphocyte entry into lymph nodes. Using luminescent conjugated polymers for histochemical PrP(Sc) detection, we identified PrP(Sc) deposits associated with HEVs in TNFR1⁻/⁻ lymph nodes. Hence, prions may enter lymph nodes by HEVs and accumulate or replicate in the absence of mature FDCs.
PLoS Pathogens 08/2012; 8(8):e1002867. · 9.13 Impact Factor
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Monika Julia Wolf,
Alexandra Hoos,
Judith Bauer,
Steffen Boettcher,
Markus Knust,
Achim Weber,
Nicole Simonavicius,
Christoph Schneider,
Matthias Lang,
Michael Stürzl,
Roland S Croner,
Andreas Konrad,
Markus G Manz,
Holger Moch,
Adriano Aguzzi,
Geert van Loo,
Manolis Pasparakis,
Marco Prinz,
Lubor Borsig, Mathias Heikenwalder
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ABSTRACT: Increased expression of the chemokine CCL2 in tumor cells correlates with enhanced metastasis, poor prognosis, and recruitment of CCR2(+)Ly6C(hi) monocytes. However, the mechanisms driving tumor cell extravasation through the endothelium remain elusive. Here, we describe CCL2 upregulation in metastatic UICC stage IV colon carcinomas and demonstrate that tumor cell-derived CCL2 activates the CCR2(+) endothelium to increase vascular permeability in vivo. CCR2 deficiency prevents colon carcinoma extravasation and metastasis. Of note, CCR2 expression on radio-resistant cells or endothelial CCR2 expression restores extravasation and metastasis in Ccr2(-/-) mice. Reduction of CCR2 expression on myeloid cells decreases but does not prevent metastasis. CCL2-induced vascular permeability and metastasis is dependent on JAK2-Stat5 and p38MAPK signaling. Our study identifies potential targets for treating CCL2-dependent metastasis.
Cancer cell 07/2012; 22(1):91-105. · 25.29 Impact Factor
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Nike Julia Krautler,
Veronika Kana,
Jan Kranich,
Yinghua Tian,
Dushan Perera,
Doreen Lemm,
Petra Schwarz,
Annika Armulik,
Jeffrey L Browning,
Michelle Tallquist,
Thorsten Buch,
José B Oliveira-Martins,
Caihong Zhu,
Mario Hermann,
Ulrich Wagner,
Robert Brink, Mathias Heikenwalder,
Adriano Aguzzi
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ABSTRACT: The differentiation of follicular dendritic cells (FDC) is essential to the remarkable microanatomic plasticity of lymphoid follicles. Here we show that FDC arise from ubiquitous perivascular precursors (preFDC) expressing platelet-derived growth factor receptor β (PDGFRβ). PDGFRβ-Cre-driven reporter gene recombination resulted in FDC labeling, whereas conditional ablation of PDGFRβ(+)-derived cells abolished FDC, indicating that FDC originate from PDGFRβ(+) cells. Lymphotoxin-α-overexpressing prion protein (PrP)(+) kidneys developed PrP(+) FDC after transplantation into PrP(-) mice, confirming that preFDC exist outside lymphoid organs. Adipose tissue-derived PDGFRβ(+) stromal-vascular cells responded to FDC maturation factors and, when transplanted into lymphotoxin β receptor (LTβR)(-) kidney capsules, differentiated into Mfge8(+)CD21/35(+)FcγRIIβ(+)PrP(+) FDC capable of trapping immune complexes and recruiting B cells. Spleens of lymphocyte-deficient mice contained perivascular PDGFRβ(+) FDC precursors whose expansion required both lymphoid tissue inducer (LTi) cells and lymphotoxin. The ubiquity of preFDC and their strategic location at blood vessels may explain the de novo generation of organized lymphoid tissue at sites of lymphocytic inflammation.
Cell 07/2012; 150(1):194-206. · 32.40 Impact Factor
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ABSTRACT: Systemic bacterial infection is rapidly recognized as an emergency state leading to neutrophil release into the circulation and increased myeloid cell production within the bone marrow. However, the mechanisms of sensing infection and subsequent translation into emergency myelopoiesis have not been defined. In this study, we demonstrate in vivo in mice that, surprisingly, selective TLR4 expression within the hematopoietic compartment fails to induce LPS-driven emergency myelopoiesis. In contrast, TLR4-expressing nonhematopoietic cells are indispensable for LPS-induced, G-CSF-mediated myelopoietic responses. Furthermore, LPS-induced emergency myelopoiesis is independent of intact IL-1RI signaling and, thus, does not require inflammasome activation. Collectively, our findings reveal a key and nonredundant role for nonhematopoietic compartment pathogen sensing that is subsequently translated into cytokine release for enhanced, demand-adapted myeloid cell production.
The Journal of Immunology 05/2012; 188(12):5824-8. · 5.79 Impact Factor
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ABSTRACT: Enteric pathogens need to grow efficiently in the gut lumen in order to cause disease and ensure transmission. The interior of the gut forms a complex environment comprising the mucosal surface area and the inner gut lumen with epithelial cell debris and food particles. Recruitment of neutrophils to the intestinal lumen is a hallmark of non-typhoidal Salmonella enterica infections in humans. Here, we analyzed the interaction of gut luminal neutrophils with S. enterica serovar Typhimurium (S. Tm) in a mouse colitis model.
Upon S. Tm(wt) infection, neutrophils transmigrate across the mucosa into the intestinal lumen. We detected a majority of pathogens associated with luminal neutrophils 20 hours after infection. Neutrophils are viable and actively engulf S. Tm, as demonstrated by live microscopy. Using S. Tm mutant strains defective in tissue invasion we show that pathogens are mostly taken up in the gut lumen at the epithelial barrier by luminal neutrophils. In these luminal neutrophils, S. Tm induces expression of genes typically required for its intracellular lifestyle such as siderophore production iroBCDE and the Salmonella pathogenicity island 2 encoded type three secretion system (TTSS-2). This shows that S. Tm at least transiently survives and responds to engulfment by gut luminal neutrophils. Gentamicin protection experiments suggest that the life-span of luminal neutrophils is limited and that S. Tm is subsequently released into the gut lumen. This "fast cycling" through the intracellular compartment of gut luminal neutrophils would explain the high fraction of TTSS-2 and iroBCDE expressing intra- and extracellular bacteria in the lumen of the infected gut.
In conclusion, live neutrophils recruited during acute S. Tm colitis engulf pathogens in the gut lumen and may thus actively engage in shaping the environment of pathogens and commensals in the inflamed gut.
PLoS ONE 01/2012; 7(4):e34812. · 4.09 Impact Factor
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Tae-Won Kang,
Tetyana Yevsa,
Norman Woller,
Lisa Hoenicke,
Torsten Wuestefeld,
Daniel Dauch,
Anja Hohmeyer,
Marcus Gereke,
Ramona Rudalska,
Anna Potapova, [......],
Jesus Gil,
Dunja Bruder,
Michael Manns,
Peter Schirmacher,
Frank Tacke,
Michael Ott,
Tom Luedde,
Thomas Longerich,
Stefan Kubicka,
Lars Zender
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ABSTRACT: Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour development in vivo. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it was reported that this 'secretory phenotype' can have pro- as well as anti-tumorigenic effects. Here we show that oncogene-induced senescence occurs in otherwise normal murine hepatocytes in vivo. Pre-malignant senescent hepatocytes secrete chemo- and cytokines and are subject to immune-mediated clearance (designated as 'senescence surveillance'), which depends on an intact CD4(+) T-cell-mediated adaptive immune response. Impaired immune surveillance of pre-malignant senescent hepatocytes results in the development of murine hepatocellular carcinomas (HCCs), thus showing that senescence surveillance is important for tumour suppression in vivo. In accordance with these observations, ras-specific Th1 lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of Nras(G12V). We also found that CD4(+) T cells require monocytes/macrophages to execute the clearance of senescent hepatocytes. Our study indicates that senescence surveillance represents an important extrinsic component of the senescence anti-tumour barrier, and illustrates how the cellular senescence program is involved in tumour immune surveillance by mounting specific immune responses against antigens expressed in pre-malignant senescent cells.
Nature 11/2011; 479(7374):547-51. · 36.28 Impact Factor
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ABSTRACT: Chronic pancreatitis is a severe inflammation of the pancreas associated with destruction of the parenchyma, fibrosis, and persistent abdominal pain. Cyclooxygenase-2 (COX-2) and COX-2-derived prostaglandins, key mediators of the inflammatory response, are elevated in patients with chronic pancreatitis. Previous studies investigated COX-2 as a therapeutic target. These reports showed a reduced pathology in COX-2-deficient mice with a better outcome. Here we compared the role of COX-2 in acute and chronic pancreatic inflammation using the same COX-2(-/-) mouse model of cerulein-induced pancreatitis. In a setting of acute pancreatitis, juvenile COX-2(-/-) mice exhibited a reduced histopathological score compared with wild-type littermates; on the contrary, adult mice did not show any difference in the development of the disease. Similarly, in a setting of chronic pancreatitis induced over a period of 4 wk, adult mice of the two strains showed comparable histological score and collagen deposition. However, the abundance of mRNAs coding for profibrotic genes, such as collagen, α-smooth muscle actin, and transforming growth factor-β was consistently lower in COX-2(-/-) mice. In addition, comparable histological scores and collagen deposition were observed in wild-type mice treated with a COX-2 inhibitor. We conclude that, in contrast to what was observed in the rat pancreatitis models, COX-2 has a limited and age-dependent effect on inflammatory processes in the mouse pancreas. These results suggest that COX-2 modulates the inflammatory process during the development of pancreatitis in a species-specific manner. Thus the pathophysiological roles of COX-2 and its therapeutic implications in patients with pancreatitis should be reexamined.
AJP Gastrointestinal and Liver Physiology 03/2011; 300(6):G968-75. · 3.43 Impact Factor
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Advances in experimental medicine and biology 01/2011; 691:231-49. · 1.09 Impact Factor
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Johannes Haybaeck, Mathias Heikenwalder,
Britta Klevenz,
Petra Schwarz,
Ilan Margalith,
Claire Bridel,
Kirsten Mertz,
Elizabeta Zirdum,
Benjamin Petsch,
Thomas J Fuchs,
Lothar Stitz,
Adriano Aguzzi
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ABSTRACT: Prions, the agents causing transmissible spongiform encephalopathies, colonize the brain of hosts after oral, parenteral, intralingual, or even transdermal uptake. However, prions are not generally considered to be airborne. Here we report that inbred and crossbred wild-type mice, as well as tga20 transgenic mice overexpressing PrP(C), efficiently develop scrapie upon exposure to aerosolized prions. NSE-PrP transgenic mice, which express PrP(C) selectively in neurons, were also susceptible to airborne prions. Aerogenic infection occurred also in mice lacking B- and T-lymphocytes, NK-cells, follicular dendritic cells or complement components. Brains of diseased mice contained PrP(Sc) and transmitted scrapie when inoculated into further mice. We conclude that aerogenic exposure to prions is very efficacious and can lead to direct invasion of neural pathways without an obligatory replicative phase in lymphoid organs. This previously unappreciated risk for airborne prion transmission may warrant re-thinking on prion biosafety guidelines in research and diagnostic laboratories.
PLoS Pathogens 01/2011; 7(1):e1001257. · 9.13 Impact Factor
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ABSTRACT: There is growing evidence that chronic inflammatory processes are involved in triggering the sequence from chronic liver injury to liver fibrosis, ultimately leading to liver cancer. In the last years this process has been recapitulated in a growing number of different mouse models. However, it has remained unclear whether and how these mouse models reflect the clinical reality of human hepatocellular carcinoma (HCC). Research with animal models but also human liver specimens has indicated that the NF-κB signaling pathway might withhold a crucial function in the mediation of chronic hepatic inflammation and the transition to HCC in humans. However, previous studies led to divergent and partly conflicting results with regards to the functional role of NF-κB in hepatocarcinogenesis. Here, we discuss a new genetic mouse model for HCC, the liver-specific TAK1 knockout mouse, which lacks the NF-κB activating kinase TAK1 specifically in parenchymal liver cells. Molecular findings in this mouse model and their possible significance for chemopreventive strategies against HCC are compared to other murine HCC models.
Oncotarget 09/2010; 1(5):373-8. · 4.78 Impact Factor
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Siegfried Hapfelmeier,
Melissa A E Lawson,
Emma Slack,
Jorum K Kirundi,
Maaike Stoel, Mathias Heikenwalder,
Julia Cahenzli,
Yuliya Velykoredko,
Maria L Balmer,
Kathrin Endt,
Markus B Geuking,
Roy Curtiss,
Kathy D McCoy,
Andrew J Macpherson
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ABSTRACT: The lower intestine of adult mammals is densely colonized with nonpathogenic (commensal) microbes. Gut bacteria induce protective immune responses, which ensure host-microbial mutualism. The continuous presence of commensal intestinal bacteria has made it difficult to study mucosal immune dynamics. Here, we report a reversible germ-free colonization system in mice that is independent of diet or antibiotic manipulation. A slow (more than 14 days) onset of a long-lived (half-life over 16 weeks), highly specific anticommensal immunoglobulin A (IgA) response in germ-free mice was observed. Ongoing commensal exposure in colonized mice rapidly abrogated this response. Sequential doses lacked a classical prime-boost effect seen in systemic vaccination, but specific IgA induction occurred as a stepwise response to current bacterial exposure, such that the antibody repertoire matched the existing commensal content.
Science 06/2010; 328(5986):1705-9. · 31.20 Impact Factor
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ABSTRACT: The mononuclear phagocyte system, particularly dendritic cells, plays several pivotal roles in the development of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Here, we demonstrate that functionally distinct dendritic cell subpopulations are present in the central nervous system during experimental autoimmune encephalomyelitis. At peak experimental autoimmune encephalomyelitis, the majority of dendritic cells consisted of a CD11b(+)F4/80(+) inflammatory dendritic cell subtype. Both granulocyte-macrophage colony-stimulating factor and chemokine (C-C motif) ligand 2 were previously suggested to recruit 'inflammatory' monocyte-derived dendritic cells to the central nervous system during experimental autoimmune encephalomyelitis. We show that intra-cerebral production of granulocyte-macrophage colony-stimulating factor leading to chemokine (C-C motif) ligand 2 induction and attraction of chemokine (C-C motif) receptor 2-positive precursors suffices to recruit dendritic cell populations identical to those observed in experimental autoimmune encephalomyelitis into the central nervous system of healthy mice. This does not occur with fms-like tyrosine kinase-3-ligand treatment. Both during experimental autoimmune encephalomyelitis and upon intra-cerebral granulocyte-macrophage colony-stimulating factor production, all myeloid dendritic cells, lymphoid dendritic cells and periphery-derived inflammatory dendritic cells stimulated T cell proliferation, whereas inflammatory dendritic cells that differentiated from central nervous system precursors inhibited T cell activation and pro-inflammatory cytokine production. Despite the capacity of granulocyte-macrophage colony-stimulating factor to induce central nervous system-derived inhibitory inflammatory dendritic cells, the administration of granulocyte-macrophage colony-stimulating factor into mice with experimental autoimmune encephalomyelitis resulted in exacerbated disease. Granulocyte-macrophage colony-stimulating factor thus has a dual role in the central nervous system: it directs both central nervous system-derived dendritic cells towards an inhibitory phenotype and recruits peripheral dendritic cells exhibiting pro-inflammatory functions.
Brain 06/2010; 133(Pt 6):1637-54. · 9.46 Impact Factor
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Kira Bettermann,
Mihael Vucur,
Johannes Haybaeck,
Christiane Koppe,
Jörn Janssen,
Felix Heymann,
Achim Weber,
Ralf Weiskirchen,
Christian Liedtke,
Nikolaus Gassler, [......],
Thomas Fuchs,
Stefan Zoller,
Stefano Cairo,
Marie-Annick Buendia,
Marco Prinz,
Shizuo Akira,
Frank Tacke, Mathias Heikenwalder,
Christian Trautwein,
Tom Luedde
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ABSTRACT: The MAP3-kinase TGF-beta-activated kinase 1 (TAK1) critically modulates innate and adaptive immune responses and connects cytokine stimulation with activation of inflammatory signaling pathways. Here, we report that conditional ablation of TAK1 in liver parenchymal cells (hepatocytes and cholangiocytes) causes hepatocyte dysplasia and early-onset hepatocarcinogenesis, coinciding with biliary ductopenia and cholestasis. TAK1-mediated cancer suppression is exerted through activating NF-kappaB in response to tumor necrosis factor (TNF) and through preventing Caspase-3-dependent hepatocyte and cholangiocyte apoptosis. Moreover, TAK1 suppresses a procarcinogenic and pronecrotic pathway, which depends on NF-kappaB-independent functions of the I kappaB-kinase (IKK)-subunit NF-kappaB essential modulator (NEMO). Therefore, TAK1 serves as a gatekeeper for a protumorigenic, NF-kappaB-independent function of NEMO in parenchymal liver cells.
Cancer cell 05/2010; 17(5):481-96. · 25.29 Impact Factor
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Achim Weber,
Regina Boger,
Binje Vick,
Toni Urbanik,
Johannes Haybaeck,
Stefan Zoller,
Andreas Teufel,
Peter H Krammer,
Joseph T Opferman,
Peter R Galle,
Marcus Schuchmann, Mathias Heikenwalder,
Henning Schulze-Bergkamen
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ABSTRACT: Regulation of hepatocellular apoptosis is crucial for liver homeostasis. Increased sensitivity of hepatocytes toward apoptosis results in chronic liver injury, whereas apoptosis resistance is linked to hepatocarcinogenesis and nonresponsiveness to therapy-induced cell death. Recently, we have demonstrated an essential role of the antiapoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) in hepatocyte survival. In mice lacking Mcl-1 specifically in hepatocytes (Mcl-1(Deltahep)), spontaneous apoptosis caused severe liver damage. Here, we demonstrate that chronically increased apoptosis of hepatocytes coincides with strong hepatocyte proliferation resulting in hepatocellular carcinoma (HCC). Liver cell tumor formation was observed in >50% of Mcl-1(Deltahep) mice already by the age of 8 months, whereas 12-month-old wild-type (wt) and heterozygous Mcl-1(flox/wt) mice lacked tumors. Tumors revealed a heterogenous spectrum ranging from small dysplastic nodules to HCC. The neoplastic nature of the tumors was confirmed by histology, expression of the HCC marker glutamine synthetase and chromosomal aberrations. Liver carcinogenesis in Mcl-1(Deltahep) mice was paralleled by markedly increased levels of Survivin, an important regulator of mitosis which is selectively overexpressed in common human cancers. Conclusion: This study provides in vivo evidence that increased apoptosis of hepatocytes not only impairs liver homeostasis but is also accompanied by hepatocyte proliferation and hepatocarcinogenesis. Our findings might have implications for understanding apoptosis-related human liver diseases.
Hepatology 04/2010; 51(4):1226-36. · 11.66 Impact Factor
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Kathrin Endt,
Bärbel Stecher,
Samuel Chaffron,
Emma Slack,
Nicolas Tchitchek,
Arndt Benecke,
Laurye Van Maele,
Jean-Claude Sirard,
Andreas J Mueller, Mathias Heikenwalder,
Andrew J Macpherson,
Richard Strugnell,
Christian von Mering,
Wolf-Dietrich Hardt
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ABSTRACT: Many enteropathogenic bacteria target the mammalian gut. The mechanisms protecting the host from infection are poorly understood. We have studied the protective functions of secretory antibodies (sIgA) and the microbiota, using a mouse model for S. typhimurium diarrhea. This pathogen is a common cause of diarrhea in humans world-wide. S. typhimurium (S. tm(att), sseD) causes a self-limiting gut infection in streptomycin-treated mice. After 40 days, all animals had overcome the disease, developed a sIgA response, and most had cleared the pathogen from the gut lumen. sIgA limited pathogen access to the mucosal surface and protected from gut inflammation in challenge infections. This protection was O-antigen specific, as demonstrated with pathogens lacking the S. typhimurium O-antigen (wbaP, S. enteritidis) and sIgA-deficient mice (TCRβ(-/-)δ(-/-), J(H) (-/-), IgA(-/-), pIgR(-/-)). Surprisingly, sIgA-deficiency did not affect the kinetics of pathogen clearance from the gut lumen. Instead, this was mediated by the microbiota. This was confirmed using 'L-mice' which harbor a low complexity gut flora, lack colonization resistance and develop a normal sIgA response, but fail to clear S. tm(att) from the gut lumen. In these mice, pathogen clearance was achieved by transferring a normal complex microbiota. Thus, besides colonization resistance ( = pathogen blockage by an intact microbiota), the microbiota mediates a second, novel protective function, i.e. pathogen clearance. Here, the normal microbiota re-grows from a state of depletion and disturbed composition and gradually clears even very high pathogen loads from the gut lumen, a site inaccessible to most "classical" immune effector mechanisms. In conclusion, sIgA and microbiota serve complementary protective functions. The microbiota confers colonization resistance and mediates pathogen clearance in primary infections, while sIgA protects from disease if the host re-encounters the same pathogen. This has implications for curing S. typhimurium diarrhea and for preventing transmission.
PLoS Pathogens 01/2010; 6(9):e1001097. · 9.13 Impact Factor
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Rowayda Peters,
Monika J Wolf,
Maries van den Broek,
Mario Nuvolone,
Stefanie Dannenmann,
Bruno Stieger,
Reto Rapold,
Daniel Konrad,
Arnold Rubin,
Joseph R Bertino,
Adriano Aguzzi, Mathias Heikenwalder,
Alexander K Knuth
[show abstract]
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ABSTRACT: Haematopoiesis is sustained by haematopoietic (HSC) and mesenchymal stem cells (MSC). HSC are the precursors for blood cells, whereas marrow, stroma, bone, cartilage, muscle and connective tissues derive from MSC. The generation of MSC from umbilical cord blood (UCB) is possible, but with low and unpredictable success. Here we describe a novel, robust stroma-free dual cell culture system for long-term expansion of primitive UCB-derived MSC.
UCB-derived mononuclear cells (MNC) or selected CD34(+) cells were grown in liquid culture in the presence of serum and cytokines. Out of 32 different culture conditions that have been tested for the efficient expansion of HSC, we identified one condition (DMEM, pooled human AB serum, Flt-3 ligand, SCF, MGDF and IL-6; further denoted as D7) which, besides supporting HSC expansion, successfully enabled long-term expansion of stromal/MSC from 8 out of 8 UCB units (5 MNC-derived and 3 CD34(+) selected cells). Expanded MSC displayed a fibroblast-like morphology, expressed several stromal/MSC-related antigens (CD105, CD73, CD29, CD44, CD133 and Nestin) but were negative for haematopoietic cell markers (CD45, CD34 and CD14). MSC stemness phenotype and their differentiation capacity in vitro before and after high dilution were preserved throughout long-term culture. Even at passage 24 cells remained Nestin(+), CD133(+) and >95% were positive for CD105, CD73, CD29 and CD44 with the capacity to differentiate into mesodermal lineages. Similarly we show that UCB derived MSC express pluripotency stem cell markers despite differences in cell confluency and culture passages. Further, we generated MSC from peripheral blood (PB) MNC of 8 healthy volunteers. In all cases, the resulting MSC expressed MSC-related antigens and showed the capacity to form CFU-F colonies.
This novel stroma-free liquid culture overcomes the existing limitation in obtaining MSC from UCB and PB enabling so far unmet therapeutic applications, which might substantially affect clinical practice.
PLoS ONE 01/2010; 5(12):e15689. · 4.09 Impact Factor
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Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2010; 6(4).
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Achim Weber,
Regina Boger,
Binje Vick,
Toni Urbanik,
Johannes Haybaeck,
Stefan Zoller,
Andreas Teufel,
Peter H. Krammer,
Joseph T. Opferman,
Peter R. Galle,
Marcus Schuchmann, Mathias Heikenwalder,
Henning Schulze-Bergkamen
[show abstract]
[hide abstract]
ABSTRACT: Regulation of hepatocellular apoptosis is crucial for liver homeostasis. Increased sensitivity of hepatocytes toward apoptosis results in chronic liver injury, whereas apoptosis resistance is linked to hepatocarcinogenesis and nonresponsiveness to therapy-induced cell death. Recently, we have demonstrated an essential role of the antiapoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) in hepatocyte survival. In mice lacking Mcl-1 specifically in hepatocytes (Mcl-1Δhep), spontaneous apoptosis caused severe liver damage. Here, we demonstrate that chronically increased apoptosis of hepatocytes coincides with strong hepatocyte proliferation resulting in hepatocellular carcinoma (HCC). Liver cell tumor formation was observed in >50% of Mcl-1Δhep mice already by the age of 8 months, whereas 12-month-old wild-type (wt) and heterozygous Mcl-1flox/wt mice lacked tumors. Tumors revealed a heterogenous spectrum ranging from small dysplastic nodules to HCC. The neoplastic nature of the tumors was confirmed by histology, expression of the HCC marker glutamine synthetase and chromosomal aberrations. Liver carcinogenesis in Mcl-1Δhep mice was paralleled by markedly increased levels of Survivin, an important regulator of mitosis which is selectively overexpressed in common human cancers. Conclusion: This study provides in vivo evidence that increased apoptosis of hepatocytes not only impairs liver homeostasis but is also accompanied by hepatocyte proliferation and hepatocarcinogenesis. Our findings might have implications for understanding apoptosis-related human liver diseases. (HEPATOLOGY 2010.)
Hepatology 11/2009; 51(4):1226 - 1236. · 11.66 Impact Factor
