scholarly journals Toll-Like Receptor-2-Mediated C-C Chemokine Receptor 3 and Eotaxin-Driven Eosinophil Influx Induced by Mycobacterium bovis BCG Pleurisy

2006 ◽  
Vol 75 (3) ◽  
pp. 1507-1511 ◽  
Author(s):  
Heloisa D'Ávila ◽  
Patrícia E. Almeida ◽  
Natália R. Roque ◽  
Hugo C. Castro-Faria-Neto ◽  
Patrícia T. Bozza
Keyword(s):  
Mycobacterium Bovis ◽  
Lipid Body ◽  
Eosinophil Infiltration ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Body Formation ◽  
Pleural Infection ◽  
Toll Like Receptor 2 ◽  
Deficient Mice ◽  
Eosinophil Accumulation

ABSTRACT An acute and persistent eosinophil infiltration is observed during Mycobacterium bovis BCG pleural infection in mice. Eosinophil accumulation, lipid body formation, and eotaxin production were significantly reduced in BCG-infected Toll-like receptor-2 (TLR2)-deficient mice compared to wild-type mice. Neutralization of eotaxin or CCR3 drastically inhibited BCG-induced eosinophil accumulation and lipid body formation, indicating that BCG-induced eosinophil recruitment and activation is largely dependent of TLR2-mediated eotaxin generation.

scholarly journals Toll-Like Receptor 2 Recognizes Orientia tsutsugamushi and Increases Susceptibility to Murine Experimental Scrub Typhus

2016 ◽  
Vol 84 (12) ◽  
pp. 3379-3387 ◽  
Author(s):  
Mohammad Gharaibeh ◽  
Monica Hagedorn ◽  
Stefanie Lilla ◽  
Matthias Hauptmann ◽  
Holger Heine ◽  
...  
Keyword(s):  
Scrub Typhus ◽  
Orientia Tsutsugamushi ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Content Type ◽  
Lethal Infection ◽  
Tnf Α ◽  
Toll Like Receptor 2 ◽  
Deficient Mice ◽  
Increased Susceptibility

Scrub typhus is a potentially lethal infection that is caused by the obligate intracellular bacteriumOrientia tsutsugamushi. The roles of Toll-like receptor 2 (TLR2) and TLR4 in innate recognition ofO. tsutsugamushihave not been elucidated. By overexpression of TLR2 or TLR4 in HEK293 cells, we demonstrated that TLR2, but not TLR4, recognizes heat-stable compounds ofO. tsutsugamushithat were sensitive to treatment with sodium hydroxide, hydrogen peroxide, and proteinase K. TLR2 was required for the secretion of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) by dendritic cells. In an intradermal mouse infection model, TLR2-deficient mice did not show impaired control of bacterial growth or reduced survival. Moreover, after intraperitoneal infection, TLR2-deficient mice were even more resistant to lethal infection than C57BL/6 wild-type mice, which showed stronger symptoms and lower survival rates during the convalescent phase. Compared to the time of reduction of bacterial loads in TLR2-deficient mice, the reduction of bacterial loads in infected organs was accelerated in wild-type mice. The higher mortality of wild-type mice was associated with increased concentrations of serum alkaline phosphatase but not aspartate aminotransferase. The transcription of mRNA for TNF-α and IL-6 decreased more rapidly in peritoneum samples from wild-type mice than in those from TLR2-deficient mice and was therefore not a correlate of increased susceptibility. Thus, although TLR2 is an important mediator of the early inflammatory response, it is dispensable for protective immunity againstO. tsutsugamushi. Increased susceptibility toO. tsutsugamushiinfection in TLR2-competent mice rather suggests a TLR2-related immunopathologic effect.

scholarly journals Tripalmitoyl-S-Glyceryl-Cysteine-Dependent OspA Vaccination of Toll-Like Receptor 2-Deficient Mice Results in Effective Protection from Borrelia burgdorferi Challenge

2003 ◽  
Vol 71 (7) ◽  
pp. 3894-3900 ◽  
Author(s):  
Alyson Yoder ◽  
Xiaohui Wang ◽  
Ying Ma ◽  
Mario T. Philipp ◽  
Marta Heilbrun ◽  
...  
Keyword(s):  
Borrelia Burgdorferi ◽  
Humoral Response ◽  
Mouse Strains ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Adjuvant Activity ◽  
Modified Lipoproteins ◽  
Toll Like Receptor 2 ◽  
Humoral Responses ◽  
Deficient Mice

ABSTRACT Toll-like receptor 2 (TLR2) is a transmembrane signal transducer for tripalmitoyl-S-glyceryl-cysteine (Pam3Cys)-modified lipoproteins, including OspA from the Lyme disease spirochete Borrelia burgdorferi. The Pam3Cys modification provides adjuvant activity for inducing humoral responses, suggesting that TLR2 could function as the adjuvant receptor for the OspA vaccine. The importance of TLR2 in the humoral response to OspA was confirmed, because overall levels of immunoglobulin G (IgG) were reduced in TLR2-deficient mice, when compared with those in wild-type mice. However, the levels of production of IgG1 were similar in both mouse strains, and the levels of induction of protective immunity were comparable. Unlipidated OspA was not immunogenic in wild-type or TLR2-deficient mice, indicating the lipid modification was active in the absence of TLR2. These findings indicate that the Pam3Cys modification of bacterial lipoprotein has adjuvant properties independent of TLR2 signaling.

scholarly journals Mechanisms of platelet-activating factor-induced lipid body formation: requisite roles for 5-lipoxygenase and de novo protein synthesis in the compartmentalization of neutrophil lipids.

1996 ◽  
Vol 183 (4) ◽  
pp. 1515-1525 ◽  
Author(s):  
P T Bozza ◽  
J L Payne ◽  
J L Goulet ◽  
P F Weller
Keyword(s):  
Actinomycin D ◽  
Platelet Activating Factor ◽  
Lipid Body ◽  
Lipid Bodies ◽  
Wild Type ◽  
Body Formation ◽  
Paf Receptor ◽  
Deficient Mice ◽  
Web 2086

Lipid bodies, lipid rich cytoplasmic inclusions, are characteristically abundant in vivo in leukocytes associated with inflammation. Because lipid bodies are potential reservoirs of esterified arachidonate and sites at which eicosanoid-forming enzymes may localize, we evaluated mechanisms of lipid body formation in neutrophils (PMN). Among receptor-mediated agonists, platelet activating factor (PAF), but not C5a, formyl-methyl-phenylalanine, interleukin 8, or leukotriene (LT) B4, induced the rapid formation of lipid bodies in PMN. This action of PAF was receptor mediated, as it was dose dependently inhibited by the PAF receptor antagonist WEB 2086 and blocked by pertussis toxin. Lipid body induction by PAF required 5-lipoxygenase (LO) activity and was inhibited by the 5-lipoxygenase-activating protein antagonist MK 886 and the 5-LO inhibitor zileuton, but not by cyclooxygenase inhibitors. Corroborating the dependency of PAF-induced lipid body formation on 5-LO, PMN and macrophages from wild-type mice, but not from 5-LO genetically deficient mice, formed lipid bodies on exposure to PAF both in vitro and in vivo within the pleural cavity. The 5-LO product inducing lipid body formation was not LTB4 but was 5(S)-hydroxyeicosatetraenoic acid [5(S)-HETE], which was active at 10-fold lower concentrations than PAF and was also inhibited by pertussis toxin but not by zileuton or WEB 2086. Furthermore, 5-HETE was equally effective in inducing lipid body formation in both wild-type and 5-LO genetically deficient mice. Both PAF- and 5(S)-HETE-induced lipid body formation were inhibited by protein kinase C (PKC) inhibitors staurosporine and chelerythrine, the phospholipase C (PLC) inhibitors D609 and U-73122, and by actinomycin D and cycloheximide. Prior stimulation of human PMN with PAF to form lipid bodies enhanced eicosanoid production in response to submaximal stimulation with the calcium ionophore A23187; and the levels of both prostaglandin (PG) E2 and LTB4 correlated with the number of lipid bodies. Furthermore, pretreatment of cells with actinomycin D or cycloheximide inhibited not only the induction of lipid body formation by PAF, but also the PAF-induced "priming" for enhanced PGE2 and LTB4 in PMN. Thus, the compartmentalization of lipids to form lipid bodies in PMN is dependent on specific cellular responses that can be PAF receptor mediated, involves signaling through 5-LO to form 5-HETE and then through PKC and PLC, and requires new protein synthesis. Since increases in lipid body numbers correlated with priming for enhanced PGE2 and LTB4 production in PMN, the induction of lipid bodies may have a role in the formation of eicosanoid mediators by leukocytes involved in inflammation.

scholarly journals Toll-like Receptor 4 Signaling in Ventilator-induced Diaphragm Atrophy

2012 ◽  
Vol 117 (2) ◽  
pp. 329-338 ◽  
Author(s):  
Willem-Jan M. Schellekens ◽  
Hieronymus W. H. van Hees ◽  
Michiel Vaneker ◽  
Marianne Linkels ◽  
P. N. Richard Dekhuijzen ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Caspase 3 ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Diaphragm Atrophy ◽  
Deficient Mice

Background Mechanical ventilation induces diaphragm muscle atrophy, which plays a key role in difficult weaning from mechanical ventilation. The signaling pathways involved in ventilator-induced diaphragm atrophy are poorly understood. The current study investigated the role of Toll-like receptor 4 signaling in the development of ventilator-induced diaphragm atrophy. Methods Unventilated animals were selected for control: wild-type (n = 6) and Toll-like receptor 4 deficient mice (n = 6). Mechanical ventilation (8 h): wild-type (n = 8) and Toll-like receptor 4 deficient (n = 7) mice.Myosin heavy chain content, proinflammatory cytokines, proteolytic activity of the ubiquitin-proteasome pathway, caspase-3 activity, and autophagy were measured in the diaphragm. Results Mechanical ventilation reduced myosin content by approximately 50% in diaphragms of wild-type mice (P less than 0.05). In contrast, ventilation of Toll-like receptor 4 deficient mice did not significantly affect diaphragm myosin content. Likewise, mechanical ventilation significantly increased interleukin-6 and keratinocyte-derived chemokine in the diaphragm of wild-type mice, but not in ventilated Toll-like receptor 4 deficient mice. Mechanical ventilation increased diaphragmatic muscle atrophy factor box transcription in both wild-type and Toll-like receptor 4 deficient mice. Other components of the ubiquitin-proteasome pathway and caspase-3 activity were not affected by ventilation of either wild-type mice or Toll-like receptor 4 deficient mice. Mechanical ventilation induced autophagy in diaphragms of ventilated wild-type mice, but not Toll-like receptor 4 deficient mice. Conclusion Toll-like receptor 4 signaling plays an important role in the development of ventilator-induced diaphragm atrophy, most likely through increased expression of cytokines and activation of lysosomal autophagy.

scholarly journals Toll-Like Receptor 2 Controls the Gamma Interferon Response to Francisella tularensis by Mouse Liver Lymphocytes

2007 ◽  
Vol 75 (11) ◽  
pp. 5338-5345 ◽  
Author(s):  
Kee-Jong Hong ◽  
Jason R. Wickstrum ◽  
Hung-Wen Yeh ◽  
Michael J. Parmely
Keyword(s):  
Francisella Tularensis ◽  
Cell Types ◽  
Gamma Interferon ◽  
Interferon Response ◽  
Interleukin 12 ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT The production of gamma interferon (IFN-γ) is a key step in the protective innate immune response to Francisella tularensis. Natural killer cells and T cells in the liver are important sources of this cytokine during primary F. tularensis infections, and interleukin-12 (IL-12) appears to be an essential coactivating cytokine for hepatic IFN-γ expression. The present study was undertaken to determine whether or not macrophages (Mφ) or dendritic cells (DC) provide coactivating signals for the liver IFN-γ response in vitro, whether IL-12 mediates these effects, and whether Toll-like receptor (TLR) signaling is essential to induce this costimulatory activity. Both bone marrow-derived Mφ and DC significantly augmented the IFN-γ response of F. tularensis-challenged liver lymphocytes in vitro. While both cell types produced IL-12p40 in response to F. tularensis challenge, only DC secreted large quantities of IL-12p70. DC from both IL-12p35-deficient and TLR2-deficient mice failed to produce IL-12p70 and did not costimulate liver lymphocytes for IFN-γ production in response to viable F. tularensis organisms. Conversely, liver lymphocytes from TLR2-deficient mice cocultured with wild-type accessory cells produced IFN-γ at levels comparable to those for wild-type hepatic lymphocytes. These findings indicate that TLR2 controls hepatic lymphocyte IFN-γ responses to F. tularensis by regulating DC IL-12 production. While Mφ also coinduced hepatic IFN-γ production in response to F. tularensis, they did so in a fashion less dependent on TLR2.

scholarly journals Toll-like receptor 9 prevents cardiac rupture after myocardial infarction in mice independently of inflammation

2016 ◽  
Vol 311 (6) ◽  
pp. H1485-H1497 ◽  
Author(s):  
Shigemiki Omiya ◽  
Yosuke Omori ◽  
Manabu Taneike ◽  
Andrea Protti ◽  
Osamu Yamaguchi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Signaling Pathway ◽  
Cardiac Fibroblasts ◽  
Cardiac Rupture ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Double Positive ◽  
Cpg Oligonucleotide ◽  
Deficient Mice ◽  
Tlr9 Signaling

We have reported that the Toll-like receptor 9 (TLR9) signaling pathway plays an important role in the development of pressure overload-induced inflammatory responses and heart failure. However, its role in cardiac remodeling after myocardial infarction has not been elucidated. TLR9-deficient and control C57Bl/6 wild-type mice were subjected to left coronary artery ligation. The survival rate 14 days postoperation was significantly lower in TLR9-deficient mice than that in wild-type mice with evidence of cardiac rupture in all dead mice. Cardiac magnetic resonance imaging showed no difference in infarct size and left ventricular wall thickness and function between TLR9-deficient and wild-type mice. There were no differences in the number of infiltrating inflammatory cells and the levels of inflammatory cytokine mRNA in infarct hearts between TLR9-deficient and wild-type mice. The number of α-smooth muscle actin (αSMA)-positive myofibroblasts and αSMA/Ki67-double-positive proliferative myofibroblasts was increased in the infarct and border areas in infarct hearts compared with those in sham-operated hearts in wild-type mice, but not in TLR9-deficient mice. The class B CpG oligonucleotide increased the phosphorylation level of NF-κB and the number of αSMA-positive and αSMA/Ki67-double-positive cells and these increases were attenuated by BAY1-7082, an NF-κB inhibitor, in cardiac fibroblasts isolated from wild-type hearts. The CpG oligonucleotide showed no effect on NF-κB activation or the number of αSMA-positive and αSMA/Ki67-double-positive cells in cardiac fibroblasts from TLR9-deficient hearts. Although the TLR9 signaling pathway is not involved in the acute inflammatory response in infarct hearts, it ameliorates cardiac rupture possibly by promoting proliferation and differentiation of cardiac fibroblasts. Listen to this article’s corresponding podcast @ http://ajpheart.podbean.com/e/tlr9-in-post-infarct-cardiac-rupture/ .

scholarly journals Impaired adrenal stress response in Toll-like receptor 2-deficient mice

2004 ◽  
Vol 101 (47) ◽  
pp. 16695-16700 ◽  
Author(s):  
S. R. Bornstein ◽  
P. Zacharowski ◽  
R. R. Schumann ◽  
A. Barthel ◽  
N. Tran ◽  
...  
Keyword(s):  
Stress Response ◽  
Toll Like Receptor ◽  
Toll Like Receptor 2 ◽  
Deficient Mice

scholarly journals Long-Term Control of Mycobacterium bovis BCG Infection in the Absence of Toll-Like Receptors (TLRs): Investigation of TLR2-, TLR6-, or TLR2-TLR4-Deficient Mice

2004 ◽  
Vol 72 (12) ◽  
pp. 6994-7004 ◽  
Author(s):  
Delphine Nicolle ◽  
Cécile Fremond ◽  
Xavier Pichon ◽  
André Bouchot ◽  
Isabelle Maillet ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
Chronic Phase ◽  
Mycobacterial Infection ◽  
Infection Period ◽  
Essentially Normal ◽  
Toll Like Receptor 2 ◽  
Deficient Mice

ABSTRACT Live mycobacteria have been reported to signal through both Toll-like receptor 2 (TLR2) and TLR4 in vitro. Here, we investigated the role of TLR2 in the long-term control of the infection by the attenuated Mycobacterium, Mycobacterium bovis BCG, in vivo. We sought to determine whether the reported initial defect of bacterial control (K. A. Heldwein et al., J. Leukoc. Biol. 74:277-286, 2003) resolved in the chronic phase of BCG infection. Here we show that TLR2-deficient mice survived a 6-month infection period with M. bovis BCG and were able to control bacterial growth. Granuloma formation, T-cell and macrophage recruitment, and activation were normal. Furthermore, the TLR2 coreceptor, TLR6, is also not required since TLR6-deficient mice were able to control chronic BCG infection. Finally, TLR2-TLR4-deficient mice infected with BCG survived the 8-month observation period. Interestingly, the adaptive response of TLR2- and/or TLR4-deficient mice seemed essentially normal on day 14 or 56 after infection, since T cells responded normally to soluble BCG antigens. In conclusion, our data demonstrate that TLR2, TLR4, or TLR6 are redundant for the control of M. bovis BCG mycobacterial infection.

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