71 results on '"Secher T"'
Search Results
52. Blockade of IL-1R signaling diminishes Paneth cell depletion and Toxoplasma gondii induced ileitis in mice.
- Author
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Villeret B, Brault L, Couturier-Maillard A, Robinet P, Vasseur V, Secher T, Dimier-Poisson I, Jacobs M, Zheng SG, Quesniaux VF, and Ryffel B
- Abstract
Interleukin 1 is a critical inflammatory mediator and involved in host defense to several pathogens. Oral T. gondii infection causes lethal ileitis in C57BL/6 (BL6) mice and serves to investigate the mechanisms of acute intestinal inflammation. Here we show that IL-1 is expressed upon oral T. gondii (76K strain) infection in the small intestine and mediates ileitis as IL-1R1 deficient mice have reduced neutrophil recruitment in the lamina propria, parasite invasion, inflammatory lesions and enhanced survival as compared to BL6 infected control mice. Protection in the absence of IL-1R1 signaling was associated with reduced IFN-γ expression and preserved Paneth cells, while these cells were eliminated in infected BL6 mice. Furthermore, blockade of IL-1 by IL-1β antibody attenuated inflammation in BL6 mice. In conclusion, IL-1 signaling contributes to the inflammatory response with increase IFN-γ expression and Paneth cell depletion upon oral T. gondii infection.
- Published
- 2013
53. Differential expression of parvalbumin in neonatal phencyclidine-treated rats and socially isolated rats.
- Author
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Kaalund SS, Riise J, Broberg BV, Fabricius K, Karlsen AS, Secher T, Plath N, and Pakkenberg B
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- Age Factors, Animals, Animals, Newborn, Autoradiography, Brain drug effects, Brain metabolism, Cell Count, Cognition Disorders etiology, Disease Models, Animal, Excitatory Amino Acid Antagonists toxicity, Gene Expression Regulation, Developmental drug effects, Male, Motor Activity drug effects, Neuroglia drug effects, Neuroglia metabolism, Neurons metabolism, Parvalbumins genetics, Phencyclidine toxicity, Phosphopyruvate Hydratase metabolism, RNA, Messenger metabolism, Rats, Schizophrenia chemically induced, Social Isolation, Brain pathology, Cognition Disorders pathology, Gene Expression Regulation, Developmental physiology, Neurons drug effects, Parvalbumins metabolism, Schizophrenia pathology
- Abstract
Decreased parvalbumin expression is a hallmark of the pathophysiology of schizophrenia and has been associated with abnormal cognitive processing and decreased network specificity. It is not known whether this decrease is due to reduced expression of the parvalbumin protein or degeneration of parvalbumin-positive interneurons (PV(+) interneurons). In this study, we examined PV(+) expression in two rat models of cognitive dysfunction in schizophrenia: the environmental social isolation (SI) and pharmacological neonatal phencyclidine (neoPCP) models. Using a stereological method, the optical fractionator, we counted neurons, PV(+) interneurons, and glial cells in the medial prefrontal cortex (mPFC) and hippocampus (HPC). In addition, we quantified the mRNA level of parvalbumin in the mPFC. There was a statistically significant reduction in the number of PV(+) interneurons (p = 0.021) and glial cells (p = 0.024) in the mPFC of neonatal phencyclidine rats, but not in SI rats. We observed no alterations in the total number of neurons, hippocampal PV(+) interneurons, parvalbumin mRNA expression or volume of the mPFC or HPC in the two models. Thus, as the total number of neurons remains unchanged following phencyclidine (PCP) treatment, we suggest that the decreased number of counted PV(+) interneurons represents a reduced parvalbumin protein expression below immunohistochemical detection limit rather than a true cell loss. Furthermore, these results indicate that the effect of neonatal PCP treatment is not limited to neuronal populations., (© 2012 International Society for Neurochemistry.)
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- 2013
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54. NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer.
- Author
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Couturier-Maillard A, Secher T, Rehman A, Normand S, De Arcangelis A, Haesler R, Huot L, Grandjean T, Bressenot A, Delanoye-Crespin A, Gaillot O, Schreiber S, Lemoine Y, Ryffel B, Hot D, Nùñez G, Chen G, Rosenstiel P, and Chamaillard M
- Subjects
- Animals, Colitis metabolism, Colitis microbiology, Colitis pathology, Colorectal Neoplasms metabolism, Colorectal Neoplasms microbiology, Colorectal Neoplasms pathology, Digestive System metabolism, Digestive System microbiology, Digestive System pathology, Disease Models, Animal, Female, Humans, Male, Metagenome, Mice, Mice, Knockout, Nod2 Signaling Adaptor Protein genetics, Pregnancy, Receptor-Interacting Protein Serine-Threonine Kinase 2, Receptor-Interacting Protein Serine-Threonine Kinases deficiency, Receptor-Interacting Protein Serine-Threonine Kinases genetics, Risk Factors, Colitis etiology, Colorectal Neoplasms etiology, Nod2 Signaling Adaptor Protein deficiency
- Abstract
Instability in the composition of gut bacterial communities (dysbiosis) has been linked to common human intestinal disorders, such as Crohn's disease and colorectal cancer. Here, we show that dysbiosis caused by Nod2 deficiency gives rise to a reversible, communicable risk of colitis and colitis-associated carcinogenesis in mice. Loss of either Nod2 or RIP2 resulted in a proinflammatory microenvironment that enhanced epithelial dysplasia following chemically induced injury. The condition could be improved by treatment with antibiotics or an anti-interleukin-6 receptor-neutralizing antibody. Genotype-dependent disease risk was communicable via maternally transmitted microbiota in both Nod2-deficient and WT hosts. Furthermore, reciprocal microbiota transplantation reduced disease risk in Nod2-deficient mice and led to long-term changes in intestinal microbial communities. Conversely, disease risk was enhanced in WT hosts that were recolonized with dysbiotic fecal microbiota from Nod2-deficient mice. Thus, we demonstrated that licensing of dysbiotic microbiota is a critical component of disease risk. Our results demonstrate that NOD2 has an unexpected role in shaping a protective assembly of gut bacterial communities and suggest that manipulation of dysbiosis is a potential therapeutic approach in the treatment of human intestinal disorders.
- Published
- 2013
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55. Genotoxicity of Escherichia coli Nissle 1917 strain cannot be dissociated from its probiotic activity.
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Olier M, Marcq I, Salvador-Cartier C, Secher T, Dobrindt U, Boury M, Bacquié V, Pénary M, Gaultier E, Nougayrède JP, Fioramonti J, and Oswald E
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- Animals, Cell Line, Colitis microbiology, Disease Models, Animal, Epithelial Cells drug effects, Escherichia coli genetics, Gene Knockout Techniques, Male, Polyketides metabolism, Rats, Rats, Wistar, Escherichia coli metabolism, Escherichia coli pathogenicity, Inflammatory Bowel Diseases therapy, Mutagens metabolism, Probiotics administration & dosage
- Abstract
Oral administration of the probiotic bacterium Escherichia coli Nissle 1917 improves chronic inflammatory bowel diseases, but the molecular basis for this therapeutic efficacy is unknown. E. coli Nissle 1917 harbors a cluster of genes coding for the biosynthesis of hybrid nonribosomal peptide-polyketide(s). This biosynthetic pathway confers the ability for bacteria to induce DNA double strand breaks in eukaryotic cells. Here we reveal that inactivation of the clbA gene within this genomic island abrogated the ability for the strain to induce DNA damage and chromosomal abnormalities in non-transformed cultured rat intestinal epithelial cells but is required for the probiotic activity of E. coli Nissle 1917. Thus, evaluation of colitis severity induced in rodent fed with E. coli Nissle 1917 or an isogenic non-genotoxic mutant demonstrated the need for a functional biosynthetic pathway both in the amelioration of the disease and in the modulation of cytokine expression. Feeding rodents with a complemented strain for which genotoxicity was restored confirmed that this biosynthetic pathway contributes to the health benefits of the probiotic by modulating its immunomodulatory properties. Our data provide additional evidence for the benefit of this currently used probiotic in colitis but remind us that an efficient probiotic may also have side effects as any other medication.
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- 2012
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56. Phencyclidine treatment increases NR2A and NR2B N-methyl-D-aspartate receptor subunit expression in rats.
- Author
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Owczarek S, Hou J, Secher T, and Kristiansen LV
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- Animals, Cognition Disorders chemically induced, Cognition Disorders physiopathology, Disease Models, Animal, Excitatory Amino Acid Antagonists toxicity, Female, Male, Pregnancy, Prosencephalon physiopathology, Rats, Rats, Sprague-Dawley, Receptors, N-Methyl-D-Aspartate metabolism, Schizophrenia physiopathology, Up-Regulation drug effects, Up-Regulation physiology, Cognition Disorders metabolism, Phencyclidine toxicity, Prosencephalon drug effects, Receptors, N-Methyl-D-Aspartate antagonists & inhibitors, Schizophrenia metabolism
- Abstract
Administration of noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist phencyclidine to rats on postnatal days 7, 9, and 11 induces apoptosis in prefrontal cortex and hippocampus. In adulthood, these animals display cognitive impairment of working memory, reversal learning and attention that are similar to clinical observations in schizophrenia. In this study, expression of different NMDAR subunits, the postsynaptic mGlu5 receptor and the connecting NMDAR-mGluR5 intracellular postsynaptic density proteins have been measured in adult rats after treatment with phencyclidine on postnatal days 7, 9, and 11. We found that these animals exhibited elevated expression in medial prefrontal cortex of the NR2A and NR2B NMDA receptor subunits in adulthood. These results indicate how behavioral changes in a developmental model for cognitive dysfunction involve changes to specific molecular subsets of the cortical glutamate system.
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- 2011
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57. Remote control of intestinal tumorigenesis by innate immunity.
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Secher T, Gaillot O, Ryffel B, and Chamaillard M
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- Animals, Cell Transformation, Neoplastic pathology, Crohn Disease pathology, Humans, Immunity, Innate immunology, Intestinal Neoplasms pathology, Cell Transformation, Neoplastic immunology, Crohn Disease immunology, Intestinal Neoplasms immunology
- Abstract
Chronic intestinal inflammation has been linked to the development of colorectal cancer. Recent studies suggest that during chronic inflammation, the innate immune system may facilitate colon tumorigenesis in genetically predisposed individuals in response to certain indigenous microorganisms and/or cell remnants. In these individuals, therapeutic approaches that reroute the innate immune system's inflammatory and antimicrobial activities might help prevent colon tumorigenesis and metastasis.
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- 2010
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58. Local and remote tissue injury upon intestinal ischemia and reperfusion depends on the TLR/MyD88 signaling pathway.
- Author
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Victoni T, Coelho FR, Soares AL, de Freitas A, Secher T, Guabiraba R, Erard F, de Oliveira-Filho RM, Vargaftig BB, Lauvaux G, Kamal MA, Ryffel B, Moser R, and Tavares-de-Lima W
- Subjects
- Animals, Bacteremia, Bacteria immunology, Bacterial Toxins immunology, Capillary Permeability, Histocytochemistry, Interleukin-1beta analysis, Intestines pathology, Ischemia pathology, Lung pathology, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, Microscopy, Myeloid Differentiation Factor 88 deficiency, Neutrophils immunology, Reperfusion Injury pathology, Survival Analysis, Tumor Necrosis Factor-alpha analysis, Intestinal Diseases complications, Intestinal Diseases pathology, Ischemia complications, Lung Diseases pathology, Myeloid Differentiation Factor 88 immunology, Reperfusion Injury complications, Toll-Like Receptors immunology
- Abstract
Innate immune responses against microorganisms may be mediated by Toll-like receptors (TLRs). Intestinal ischemia-reperfusion (i-I/R) leads to the translocation of bacteria and/or bacterial products such as endotoxin, which activate TLRs leading to acute intestinal and lung injury and inflammation observed upon gut trauma. Here, we investigated the role of TLR activation by using mice deficient for the common TLR adaptor protein myeloid differentiation factor 88 (MyD88) on local and remote inflammation following intestinal ischemia. Balb/c and MyD88(-/-) mice were subjected to occlusion of the superior mesenteric artery (45 min) followed by intestinal reperfusion (4 h). Acute neutrophil recruitment into the intestinal wall and the lung was significantly diminished in MyD88(-/-) after i-I/R, which was confirmed microscopically. Diminished neutrophil recruitment was accompanied with reduced concentration of TNF-alpha and IL-1beta level. Furthermore, diminished microvascular leak and bacteremia were associated with enhanced survival of MyD88(-/-) mice. However, neither TNF-alpha nor IL-1beta neutralization prevented neutrophil recruitment into the lung but attenuated intestinal inflammation upon i-I/R. In conclusion, our data demonstrate that disruption of the TLR/MyD88 pathway in mice attenuates acute intestinal and lung injury, inflammation, and endothelial damage allowing enhanced survival.
- Published
- 2010
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59. Parasite-derived plasma microparticles contribute significantly to malaria infection-induced inflammation through potent macrophage stimulation.
- Author
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Couper KN, Barnes T, Hafalla JC, Combes V, Ryffel B, Secher T, Grau GE, Riley EM, and de Souza JB
- Subjects
- Animals, CD40 Antigens immunology, Cell Separation, Cell-Derived Microparticles parasitology, Cell-Derived Microparticles ultrastructure, Enzyme-Linked Immunosorbent Assay, Erythrocytes immunology, Female, Flow Cytometry, Fluorescent Antibody Technique, Host-Parasite Interactions immunology, Inflammation parasitology, Macrophages immunology, Macrophages parasitology, Malaria parasitology, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Electron, Scanning, Plasmodium berghei immunology, Tumor Necrosis Factor-alpha immunology, Cell-Derived Microparticles immunology, Erythrocytes parasitology, Inflammation immunology, Macrophage Activation immunology, Malaria immunology
- Abstract
There is considerable debate as to the nature of the primary parasite-derived moieties that activate innate pro-inflammatory responses during malaria infection. Microparticles (MPs), which are produced by numerous cell types following vesiculation of the cellular membrane as a consequence of cell death or immune-activation, exert strong pro-inflammatory activity in other disease states. Here we demonstrate that MPs, derived from the plasma of malaria infected mice, but not naive mice, induce potent activation of macrophages in vitro as measured by CD40 up-regulation and TNF production. In vitro, these MPs induced significantly higher levels of macrophage activation than intact infected red blood cells. Immunofluorescence staining revealed that MPs contained significant amounts of parasite material indicating that they are derived primarily from infected red blood cells rather than platelets or endothelial cells. MP driven macrophage activation was completely abolished in the absence of MyD88 and TLR-4 signalling. Similar levels of immunogenic MPs were produced in WT and in TNF(-/-), IFN-gamma(-/-), IL-12(-/-) and RAG-1(-/-) malaria-infected mice, but were not produced in mice injected with LPS, showing that inflammation is not required for the production of MPs during malaria infection. This study therefore establishes parasitized red blood cell-derived MPs as a major inducer of systemic inflammation during malaria infection, raising important questions about their role in severe disease and in the generation of adaptive immune responses.
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- 2010
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60. Soluble NCAM.
- Author
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Secher T
- Subjects
- Animals, Humans, Mood Disorders metabolism, Neoplasms metabolism, Neural Cell Adhesion Molecules genetics, Neurodegenerative Diseases metabolism, Protein Isoforms genetics, Schizophrenia metabolism, Neural Cell Adhesion Molecules metabolism, Protein Isoforms metabolism
- Published
- 2010
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61. IL-17 receptor signaling is required to control polymicrobial sepsis.
- Author
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Freitas A, Alves-Filho JC, Victoni T, Secher T, Lemos HP, Sônego F, Cunha FQ, and Ryffel B
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- Animals, Cell Movement immunology, Cytokines biosynthesis, Cytokines immunology, Fever genetics, Fever immunology, Fever metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neutrophils cytology, Neutrophils immunology, Receptors, Interleukin-17 deficiency, Receptors, Interleukin-17 genetics, Receptors, Interleukin-17 immunology, Sepsis immunology, Sepsis microbiology, Signal Transduction immunology
- Abstract
Sepsis is a systemic inflammatory response resulting from the inability of the host to contain the infection locally. Previously, we demonstrated that during severe sepsis there is a marked failure of neutrophil migration to the infection site, which contributes to dissemination of infection, resulting in high mortality. IL-17 plays an important role in neutrophil recruitment. Herein, we investigated the role of IL-17R signaling in polymicrobial sepsis induced by cecal ligation and puncture (CLP). It was observed that IL-17R-deficient mice, subjected to CLP-induced non-severe sepsis, show reduced neutrophil recruitment into the peritoneal cavity, spread of infection, and increased systemic inflammatory response as compared with C57BL/6 littermates. As a consequence, the mice showed an increased mortality rate. The ability of IL-17 to induce neutrophil migration was demonstrated in vivo and in vitro. Beside its role in neutrophil recruitment to the infection focus, IL-17 enhanced the microbicidal activity of the migrating neutrophils by a mechanism dependent on NO. Therefore, IL-17 plays a critical role in host protection during polymicrobial sepsis.
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- 2009
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62. Crucial role of TNF receptors 1 and 2 in the control of polymicrobial sepsis.
- Author
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Secher T, Vasseur V, Poisson DM, Mitchell JA, Cunha FQ, Alves-Filho JC, and Ryffel B
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- Animals, Apoptosis immunology, Cell Movement, Cells, Cultured, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neutrophils cytology, Neutrophils immunology, Peritonitis genetics, Peritonitis immunology, Peritonitis metabolism, Peritonitis microbiology, Receptors, Tumor Necrosis Factor, Type I deficiency, Receptors, Tumor Necrosis Factor, Type I genetics, Receptors, Tumor Necrosis Factor, Type I metabolism, Receptors, Tumor Necrosis Factor, Type II deficiency, Receptors, Tumor Necrosis Factor, Type II genetics, Receptors, Tumor Necrosis Factor, Type II metabolism, Signal Transduction immunology, Survival Rate, Receptors, Tumor Necrosis Factor, Type I immunology, Receptors, Tumor Necrosis Factor, Type II immunology, Sepsis immunology, Sepsis microbiology
- Abstract
Sepsis is still a major cause of mortality in the intensive critical care unit and results from an overwhelming immune response to the infection. TNF signaling pathway plays a central role in the activation of innate immunity in response to pathogens. Using a model of polymicrobial sepsis by i.p. injection of cecal microflora, we demonstrate a critical role of TNFR1 and R2 activation in the deregulated immune responses and death associated with sepsis. A large and persistent production of TNF was found in wild-type (B6) mice. TNFR1/R2-deficient mice, compared with B6 mice, survive lethal polymicrobial infection with enhanced neutrophil recruitment and bacterial clearance in the peritoneal cavity. Absence of TNFR signaling leads to a decreased local and systemic inflammatory response with diminished organ injury. Furthermore, using TNFR1/R2-deficient mice, TNF was found to be responsible for a decrease in CXCR2 expression, explaining reduced neutrophil extravasation and migration to the infectious site, and in neutrophil apoptosis. In line with the clinical experience, administration of Enbrel, a TNF-neutralizing protein, induced however only a partial protection in B6 mice, with no improvement of clinical settings, suggesting that future TNF immunomodulatory strategies should target TNFR1 and R2. In conclusion, the present data suggest that the endogenous TNFR1/R2 signaling pathway in polymicrobial sepsis reduces neutrophil recruitment contributing to mortality and as opposed to pan-TNF blockade is an important therapeutic target for the treatment of polymicrobial sepsis.
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- 2009
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63. Toll-like receptor 2 is critical for induction of Reg3 beta expression and intestinal clearance of Yersinia pseudotuberculosis.
- Author
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Dessein R, Gironella M, Vignal C, Peyrin-Biroulet L, Sokol H, Secher T, Lacas-Gervais S, Gratadoux JJ, Lafont F, Dagorn JC, Ryffel B, Akira S, Langella P, Nùñez G, Sirard JC, Iovanna J, Simonet M, and Chamaillard M
- Subjects
- Animals, Cell Line, Epithelial Cells metabolism, Epithelial Cells ultrastructure, Female, Gene Deletion, Gene Expression Profiling methods, Germ-Free Life, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Electron, Transmission, Nod2 Signaling Adaptor Protein genetics, Nod2 Signaling Adaptor Protein metabolism, Pancreatitis-Associated Proteins, Peyer's Patches metabolism, Peyer's Patches ultrastructure, Reverse Transcriptase Polymerase Chain Reaction methods, Toll-Like Receptor 2 genetics, Peyer's Patches microbiology, Proteins metabolism, Signal Transduction physiology, Toll-Like Receptor 2 metabolism, Yersinia pseudotuberculosis, Yersinia pseudotuberculosis Infections metabolism
- Abstract
Objective: Yersinia pseudotuberculosis causes ileitis and mesenteric lymphadenitis by mainly invading the Peyer's patches that are positioned in the terminal ileum. Whereas toll-like-receptor 2 (TLR2) controls mucosal inflammation by detecting certain microbiota-derived signals, its exact role in protecting Peyer's patches against bacterial invasion has not been defined., Design: Wild-type, Tlr2-, Nod2- and MyD88-deficient animals were challenged by Y pseudotuberculosis via the oral or systemic route. The role of microbiota in conditioning Peyer's patches against Yersinia through TLR2 was assessed by delivering, ad libitum, exogenous TLR2 agonists in drinking water to germ-free and streptomycin-treated animals. Bacterial eradication from Peyer's patches was measured by using a colony-forming unit assay. Expression of cryptdins and the c-type lectin Reg3 beta was quantified by quantitative reverse transcriptase polymerase chain reaction analysis., Results: Our data demonstrated that Tlr2-deficient mice failed to limit Yersinia dissemination from the Peyer's patches and succumbed to sepsis independently of nucleotide-binding and oligomerisation domain 2 (NOD2). Recognition of both microbiota-derived and myeloid differentiation factor 88 (MyD88)-mediated elicitors was found to be critically involved in gut protection against Yersinia-induced lethality, while TLR2 was dispensable to systemic Yersinia infection. Gene expression analyses revealed that optimal epithelial transcript level of the anti-infective Reg3 beta requires TLR2 activation. Consistently, Yersinia infection triggered TLR2-dependent Reg3 beta expression in Peyer's patches. Importantly, oral treatment with exogenous TLR2 agonists in germ-free animals was able to further enhance Yersinia-induced expression of Reg3 beta and to restore intestinal resistance to Yersinia. Lastly, genetic ablation of Reg3 beta resulted in impaired clearance of the bacterial load in Peyer's patches., Conclusions: TLR2/REG3 beta is thus an essential component in conditioning epithelial defence signalling pathways against bacterial invasion.
- Published
- 2009
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64. Radioresistant cells expressing TLR5 control the respiratory epithelium's innate immune responses to flagellin.
- Author
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Janot L, Sirard JC, Secher T, Noulin N, Fick L, Akira S, Uematsu S, Didierlaurent A, Hussell T, Ryffel B, and Erard F
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- Adaptor Proteins, Vesicular Transport genetics, Administration, Intranasal, Animals, Bronchoalveolar Lavage Fluid cytology, Bronchoconstriction immunology, Cell Movement genetics, Cell Movement immunology, Chemokines genetics, Chemokines metabolism, Cytokines genetics, Cytokines metabolism, Epithelial Cells metabolism, Gene Expression immunology, Inflammation immunology, Inflammation metabolism, Lung immunology, Lung metabolism, Lung pathology, Macrophages, Alveolar immunology, Macrophages, Alveolar metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88 genetics, Neutrophils cytology, Peroxidase metabolism, Plethysmography, Whole Body, Radiation Chimera immunology, Radiation Chimera metabolism, Toll-Like Receptor 5 deficiency, Toll-Like Receptor 5 genetics, Epithelial Cells immunology, Flagellin immunology, Immunity, Innate immunology, Radiation Tolerance, Respiratory Mucosa immunology, Toll-Like Receptor 5 metabolism
- Abstract
Bacterial products (such as endotoxins and flagellin) trigger innate immune responses through TLRs. Flagellin-induced signalling involves TLR5 and MyD88 and, according to some reports, TLR4. Whereas epithelial and dendritic cells are stimulated by flagellin in vitro, the cell contribution to the in vivo response is still unclear. Here, we studied the respective roles of radioresistant and radiosensitive cells in flagellin-induced airway inflammation in mice. We found that i.n. delivery of flagellin elicits a transient change in respiratory function and an acute, pro-inflammatory response in the lungs, characterized by TLR5- and MyD88-dependent chemokine secretion and neutrophil recruitment. In contrast, TLR4, CD14 and TRIF were not essential for flagellin-mediated responses, indicating that TLR4 does not cooperate with TLR5 in the lungs. Respiratory function, chemokine secretion and airway infiltration by neutrophils were dependent on radioresistant, TLR5-expressing cells. Furthermore, lung haematopoietic cells also responded to flagellin by activating TNF-alpha production. We suggest that the radioresistant lung epithelial cells are essential for initiating early, TLR5-dependent signalling in response to flagellin and thus triggering the lung's innate immune responses.
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- 2009
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65. Effect of an NCAM mimetic peptide FGL on impairment in spatial learning and memory after neonatal phencyclidine treatment in rats.
- Author
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Secher T, Berezin V, Bock E, and Glenthøj B
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- Animals, Female, Male, Neural Cell Adhesion Molecules administration & dosage, Neural Cell Adhesion Molecules pharmacology, Phencyclidine administration & dosage, Pregnancy, Rats, Rats, Sprague-Dawley, Reversal Learning drug effects, Animals, Newborn psychology, Memory drug effects, Neural Cell Adhesion Molecules agonists, Phencyclidine pharmacology
- Abstract
The FGL peptide is a neural cell adhesion molecule-derived fibroblast growth factor receptor agonist. FGL has both neurotrophic and memory enhancing properties. Neonatal phencyclidine (PCP) treatment on postnatal days 7, 9, and 11 has been shown to result in long-lasting behavioral abnormalities, including cognitive impairment relevant to schizophrenia. The present study investigated the effect of FGL on spatial learning and memory deficits induced by neonatal PCP treatment. Rat pups were treated with 30 mg/kg PCP on postnatal days 7, 9, and 11. Additionally, the rats were subjected to a chronic FGL treatment regimen where FGL was administered throughout development. Rats were tested as adults for spatial reference memory, reversal learning, and working memory in the Morris water maze. The PCP-treated rats demonstrated a robust impairment in working memory and reversal learning. However, the long-term memory component of the reference memory task was not affected by PCP. Chronic FGL treatment had no effect on the reversal learning impairment but ameliorated the working memory deficits almost to the levels of the control groups. In conclusion, the results suggest that the neonatal PCP treatment produced deficits in cognition relevant to schizophrenia. Moreover, working memory function was selectively protected by the neurotrophic peptide, FGL.
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- 2009
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66. CD14 works with toll-like receptor 2 to contribute to recognition and control of Listeria monocytogenes infection.
- Author
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Janot L, Secher T, Torres D, Maillet I, Pfeilschifter J, Quesniaux VF, Landmann R, Ryffel B, and Erard F
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- Animals, Immunity, Innate, Interleukin-12 Subunit p40 biosynthesis, Interleukin-6 biosynthesis, Lipopolysaccharide Receptors genetics, Listeria monocytogenes, Liver metabolism, Liver pathology, Macrophages metabolism, Mice, Mice, Inbred C57BL, NF-kappa B metabolism, Nitric Oxide biosynthesis, Nitric Oxide Synthase Type II metabolism, Specific Pathogen-Free Organisms, Toll-Like Receptor 2 genetics, Tumor Necrosis Factor-alpha biosynthesis, Lipopolysaccharide Receptors immunology, Listeriosis immunology, Toll-Like Receptor 2 metabolism
- Abstract
Toll-like receptor 2 (TLR2) signaling has been shown to contribute to resistance to Listeria monocytogenes infection, as TLR2-deficient mice have a heightened susceptibility to infection with this organism. Because CD14 may associate with TLR2, we investigated the role of CD14 in Listeria responses. In both CD14-deficient and TLR2-deficient macrophages, nuclear factor kappaB translocation; CD40 and CD86; and the production of interleukin (IL)-12, IL-6, tumor necrosis factor, and nitric oxide are reduced. The absence of CD14 augmented susceptibility to Listeria infection, reduced survival, and diminished bacterial clearance, as observed in TLR2-deficient mice. Compared with C57BL/6 control mice, CD14-deficient mice were observed to have a greater number of hepatic microabscesses containing abundant neutrophils, these abscesses were larger in size, and there was reduced inducible nitric oxide synthase expression. Further, mice that are both CD14 deficient and TLR2 deficient display susceptibility to infection that is comparable to that of mice deficient in either CD14 or TLR2 alone. Therefore, the present data demonstrate the role of CD14 and TLR2 in the recognition and control of Listeria infection and host resistance.
- Published
- 2008
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67. WITHDRAWN: Soluble NCAM.
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Secher T
- Published
- 2008
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68. Toll-like receptor and tumour necrosis factor dependent endotoxin-induced acute lung injury.
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Togbe D, Schnyder-Candrian S, Schnyder B, Doz E, Noulin N, Janot L, Secher T, Gasse P, Lima C, Coelho FR, Vasseur V, Erard F, Ryffel B, Couillin I, and Moser R
- Subjects
- Animals, Bronchoconstriction, Cytokines immunology, Enzyme Activation, Humans, Lipopolysaccharides, Mice, Mice, Transgenic, Pneumonia metabolism, p38 Mitogen-Activated Protein Kinases metabolism, Lung immunology, MAP Kinase Signaling System, Pneumonia immunology, Toll-Like Receptors metabolism, Tumor Necrosis Factor-alpha metabolism
- Abstract
Recent studies on endotoxin/lipopolysaccharide (LPS)-induced acute inflammatory response in the lung are reviewed. The acute airway inflammatory response to inhaled endotoxin is mediated through Toll-like receptor 4 (TLR4) and CD14 signalling as mice deficient for TLR4 or CD14 are unresponsive to endotoxin. Acute bronchoconstriction, tumour necrosis factor (TNF), interleukin (IL)-12 and keratinocyte-derived chemokine (KC) production, protein leak and neutrophil recruitment in the lung are abrogated in mice deficient for the adaptor molecules myeloid differentiation factor 88 (MyD88) and Toll/Interleukin-1 receptor (TIR)-domain-containing adaptor protein (TIRAP), but independent of TIR-domain-containing adaptor-inducing interferon-beta (TRIF). In particular, LPS-induced TNF is required for bronchoconstriction, but dispensable for inflammatory cell recruitment. Lipopolysaccharide induces activation of the p38 mitogen-activated protein kinase (MAPK). Inhibition of pulmonary MAPK activity abrogates LPS-induced TNF production, bronchoconstriction, neutrophil recruitment into the lungs and broncho-alveolar space. In conclusion, TLR4-mediated, bronchoconstriction and acute inflammatory lung pathology to inhaled endotoxin are dependent on TLR4/CD14/MD2 expression using the adapter proteins TIRAP and MyD88, while TRIF, IL-1R1 or IL-18R signalling pathways are dispensable. Further downstream in this axis of signalling, TNF blockade reduces only acute bronchoconstriction, while MAPK inhibition abrogates completely endotoxin-induced inflammation.
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- 2007
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69. Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection.
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Zalevsky J, Secher T, Ezhevsky SA, Janot L, Steed PM, O'Brien C, Eivazi A, Kung J, Nguyen DH, Doberstein SK, Erard F, Ryffel B, and Szymkowski DE
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- Animals, Arthritis, Experimental pathology, Arthritis, Experimental prevention & control, Caspase Inhibitors, Caspases metabolism, Cell Line, Tumor, Female, Humans, Inflammation Mediators metabolism, Interleukin-8 antagonists & inhibitors, Interleukin-8 blood, Interleukin-8 metabolism, Listeriosis genetics, Listeriosis pathology, Male, Membrane Proteins antagonists & inhibitors, Membrane Proteins biosynthesis, Membrane Proteins physiology, Mice, Mice, Inbred BALB C, Mice, Inbred DBA, Paracrine Communication immunology, Recombinant Proteins antagonists & inhibitors, Recombinant Proteins biosynthesis, Recombinant Proteins pharmacology, Solubility, Tumor Necrosis Factor-alpha genetics, U937 Cells, Arthritis, Experimental immunology, Immunity, Innate genetics, Inflammation Mediators physiology, Listeriosis immunology, Tumor Necrosis Factor-alpha antagonists & inhibitors, Tumor Necrosis Factor-alpha physiology
- Abstract
TNF is a pleiotropic cytokine required for normal development and function of the immune system; however, TNF overexpression also induces inflammation and is associated with autoimmune diseases. TNF exists as both a soluble and a transmembrane protein. Genetic studies in mice have suggested that inflammation in disease models involves soluble TNF (solTNF) and that maintenance of innate immune function involves transmembrane TNF (tmTNF). These findings imply that selective pharmacologic inhibition of solTNF may be anti-inflammatory and yet preserve innate immunity to infection. To address this hypothesis, we now describe dominant-negative inhibitors of TNF (DN-TNFs) as a new class of biologics that selectively inhibits solTNF. DN-TNFs blocked solTNF activity in human and mouse cells, a human blood cytokine release assay, and two mouse arthritis models. In contrast, DN-TNFs neither inhibited the activity of human or mouse tmTNF nor suppressed innate immunity to Listeria infection in mice. These results establish DN-TNFs as the first selective inhibitors of solTNF, demonstrate that inflammation in mouse arthritis models is primarily driven by solTNF, and suggest that the maintenance of tmTNF activity may improve the therapeutic index of future anti-inflammatory agents.
- Published
- 2007
- Full Text
- View/download PDF
70. Low-field magnetic resonance imaging of the lumbar spine: reliability of qualitative evaluation of disc and muscle parameters.
- Author
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Solgaard Sorensen J, Kjaer P, Jensen ST, and Andersen P
- Subjects
- Adult, Female, Humans, Intervertebral Disc Displacement complications, Male, Muscular Diseases etiology, Observer Variation, Reproducibility of Results, Intervertebral Disc Displacement diagnosis, Lumbar Vertebrae, Magnetic Resonance Imaging, Muscular Diseases diagnosis
- Abstract
Purpose: To determine the intra- and interobserver reliability in grading disc and muscle parameters using low-field magnetic resonance imaging (MRI)., Material and Methods: MRI scans of 100 subjects representative of the general population were evaluated blindly by two radiologists. Criteria for grading lumbar discs were based on the spinal nomenclature of the Combined Task Force and the literature. Consensus in rating was achieved by evaluating 50 MRI examinations in tandem. The remaining 50 examinations were evaluated independently by the observers to determine interobserver agreement and re-evaluated by one of the observers to determine intra-observer agreement., Results: Intra- and interobserver agreement was substantial when grading changes in the lumbar discs. Interobserver agreement was fair to moderate in grading the lumbar muscles, whereas intra-observer agreement was almost perfect., Conclusion: Convincing reliability was found in the evaluation of disc- and muscle-related MRI variables.
- Published
- 2006
- Full Text
- View/download PDF
71. Molecular cloning of a functional allatostatin gut/brain receptor and an allatostatin preprohormone from the silkworm Bombyx mori.
- Author
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Secher T, Lenz C, Cazzamali G, Sørensen G, Williamson M, Hansen GN, Svane P, and Grimmelikhuijzen CJ
- Subjects
- Amino Acid Sequence, Animals, Blotting, Northern, Blotting, Southern, Bombyx, CHO Cells, Cloning, Molecular, Cricetinae, DNA, Complementary metabolism, Dose-Response Relationship, Drug, Drosophila, Evolution, Molecular, Exons, Introns, Kinetics, Molecular Sequence Data, Phylogeny, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Sequence Homology, Amino Acid, Signal Transduction, Tissue Distribution, Transfection, Brain metabolism, Digestive System metabolism, Drosophila Proteins, Hormones genetics, Insect Proteins, Neuropeptides, Protein Precursors genetics, Receptors, Cell Surface chemistry, Receptors, Cell Surface genetics, Receptors, Cell Surface metabolism, Receptors, G-Protein-Coupled, Receptors, Neuropeptide
- Abstract
The cockroach-type or A-type allatostatins are inhibitory insect neuropeptides with the C-terminal sequence Tyr/Phe-X-Phe-Gly-Leu-NH(2). Here, we have cloned an A-type allatostatin receptor from the silkworm Bombyx mori (BAR). BAR is 361 amino acid residues long, has seven transmembrane domains, shows 60% amino acid residue identity with the first Drosophila allatostatin receptor (DAR-1), and 48% identity with the second Drosophila allatostatin receptor (DAR-2). The BAR gene has two introns and three exons. These two introns coincide with and have the same intron phasing as two introns in the DAR-1 and DAR-2 genes, showing that the three receptors are not only structurally but also evolutionarily related. Furthermore, we have cloned a Bombyx allatostatin preprohormone that contains eight different A-type allatostatins. Chinese hamster ovary cells permanently transfected with BAR DNA react on the addition of 4 x 10(-9)M Bombyx A-type allatostatins with a second messenger cascade (measured as bioluminescence), showing that BAR is a functional A-type allatostatin receptor. Southern blots suggest that Bombyx has at least one other BAR-related gene in addition to the BAR gene described in this paper. Northern blots and quantitative reverse transcriptase-polymerase chain reaction of different larval tissues show that BAR mRNA is mainly expressed in the gut and to a much lesser extent in the brain. To our knowledge, this is the first report on the molecular cloning and functional expression of an insect gut/brain peptide hormone receptor.
- Published
- 2001
- Full Text
- View/download PDF
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