The Experts below are selected from a list of 46179 Experts worldwide ranked by ideXlab platform
Samithamby Jeyaseelan - One of the best experts on this subject based on the ideXlab platform.
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intrapulmonary g csf rescues neutrophil recruitment to the lung and neutrophil release to blood in gram negative Bacterial Infection in mcp 1 mice
Journal of Immunology, 2012Co-Authors: Gayathriy Balamayooran, Samithamby Jeyaseelan, Pal Pacher, Sanjay Batra, Balamayooran Theivanthiran, Shanshan CaiAbstract:We previously demonstrated that MCP-1 is important for E. coli–induced neutrophil migration to the lungs. However, E. coli neither disseminates nor induces death in mice. Furthermore, the cell types and the host defense mechanisms that contribute to MCP-1–dependent neutrophil trafficking have not been defined. In this study, we sought to explore the cell types and the mechanisms associated with Klebsiella pneumoniae–mediated MCP-1–dependent neutrophil influx. MCP-1−/− mice are more susceptible to pulmonary K. pneumoniae Infection and show higher Bacterial burden in the lungs and dissemination. MCP-1−/− mice also display attenuated neutrophil influx, cytokine/chemokine production, and activation of NF-κB and MAPKs following intratracheal K. pneumoniae Infection. rMCP-1 treatment in MCP-1−/− mice following K. pneumoniae Infection rescued impairment in survival, Bacterial clearance, and neutrophil accumulation in the lung. Neutrophil numbers in the blood of MCP-1−/− mice were associated with G-CSF concentrations in bronchoalveolar lavage fluid and blood. Bone marrow or resident cell–derived MCP-1 contributed to Bacterial clearance, neutrophil accumulation, and cytokine/chemokine production in the lungs following Infection. Furthermore, exogenous MCP-1 dose dependently increased neutrophil counts and G-CSF concentrations in the blood. Intriguingly, administration of intratracheal rG-CSF to MCP-1−/− mice after K. pneumoniae Infection rescued survival, Bacterial clearance and dissemination, and neutrophil influx in MCP-1−/− mice. Collectively, these novel findings unveil an unrecognized role of MCP-1 in neutrophil-mediated host immunity during K. pneumoniae pneumonia and illustrate that G-CSF could be used to rescue impairment in host immunity in individuals with absent or malfunctional MCP-1.
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nlrc4 inflammasome mediated production of il 1β modulates mucosal immunity in the lung against gram negative Bacterial Infection
Journal of Immunology, 2012Co-Authors: Sanjay Batra, Samithamby Jeyaseelan, Pal Pacher, Nobuko WakamatsuAbstract:Bacterial flagellin is critical to mediate NLRC4 inflammasome-dependent caspase-1 activation. However, Shigella flexneri, a nonflagellated bacterium, and a flagellin (fliC) knockout strain of Pseudomonas aeruginosa are known to activate NLRC4 in bone marrow-derived macrophages. Furthermore, the flagellin-deficient fliC strain of P. aeruginosa was used in a mouse model of peritonitis to show the requirement of NLRC4. In a model of pulmonary P. aeruginosa Infection, flagellin was shown to be essential for the induction of NLRC4-dependent caspase-1 activation. Moreover, in all P. aeruginosa studies, IL-1β production was attenuated in NLRC4−/− mice; however, the role of IL-1β in NLRC4-mediated innate immunity in the lungs against a nonflagellated bacterium was not explored. In this article, we report that NLRC4 is important for host survival and Bacterial clearance, as well as neutrophil-mediated inflammation in the lungs following Klebsiella pneumoniae Infection. NLRC4 is essential for K. pneumoniae-induced production of IL-1β, IL-17A, and neutrophil chemoattractants (keratinocyte cell-derived chemokines, MIP-2, and LPS-induced CXC chemokines) in the lungs. NLRC4 signaling in hematopoietic cells contributes to K. pneumoniae-induced lung inflammation. Furthermore, exogenous IL-1β, but not IL-18 or IL-17A, partially rescued survival, neutrophil accumulation, and cytokine/chemokine expression in the lungs of NLRC4−/− mice following infectious challenge. Furthermore, IL-1R1−/− mice displayed a decrease in neutrophilic inflammation in the lungs postInfection. Taken together, these findings provide novel insights into the role of NLRC4 in host defense against K. pneumoniae Infection.
Puhong Zhang - One of the best experts on this subject based on the ideXlab platform.
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pctr1 ameliorates lipopolysaccharide induced acute inflammation and multiple organ damage via regulation of linoleic acid metabolism by promoting fads1 fasds2 elov2 expression and reducing pla2 expression
Laboratory Investigation, 2020Co-Authors: Hui Li, Xinyu Li, Chao Tian, Yang Tian, Xinyang Wang, Puhong ZhangAbstract:Gram-Negative Bacterial Infection causes an excessive inflammatory response and acute organ damage or dysfunction due to its outer membrane component, lipopolysaccharide (LPS). Protectin conjugates in tissue regeneration 1 (PCTR1), an endogenous lipid mediator, exerts fundamental anti-inflammation and pro-resolution during Infection. In the present study, we examined the properties of PCTR1 on the systemic inflammatory response, organic morphological damage and dysfunction, and serum metabolic biomarkers in an LPS-induced acute inflammatory mouse model. The results show that PCTR1 reduced serum inflammatory factors and ameliorated morphological damage and dysfunction of the lung, liver, kidney, and ultimately improved the survival rate of LPS-induced acute inflammation in mice. In addition, metabolomics analysis and high performance liquid chromatography-mass spectrometry revealed that LPS-stimulated serum linoleic acid (LA), arachidonic acid (AA), and prostaglandin E2 (PGE2) levels were significantly altered by PCTR1. Moreover, PCTR1 upregulated LPS-inhibited fatty acid desaturase 1 (FADS1), fatty acid desaturase 2 (FADS2), and elongase of very long chain fatty acids 2 (ELOVL2) expression, and downregulated LPS-stimulated phospholipase A2 (PLA2) expression to increase the intrahepatic content of AA. However, these effects of PCTR1 were partially abrogated by a lipoxin A4 receptor (ALX) antagonist (BOC-2). In summary, via the activation of ALX, PCTR1 promotes the conversion of LA to AA through upregulation of FADS1, FADS2, and ELOVL2 expression, and inhibits the conversion of bound AA into free AA through downregulation of PLA2 expression to decrease the serum AA and PGE2 levels. PCTR1, via the activation of the lipoxin A4 receptor, promotes the conversion of linoleic acid to arachidonic acid (AA) through upregulation of the desaturases FADS1, FADS2, and ELOVL2 expression. It also inhibits the conversion of bound AA into free AA through downregulation of phospholipase A2 expression, resulting in decreases in serum AA and prostaglandin E2 levels, resulting in an anti-inflammatory effect and organ protection.
Marina A Freudenberg - One of the best experts on this subject based on the ideXlab platform.
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tlr4 induced ifn γ production increases tlr2 sensitivity and drives gram negative sepsis in mice
Journal of Experimental Medicine, 2008Co-Authors: Stephan Spiller, Marina A Freudenberg, Greg Elson, Ruth Ferstl, Stefan Dreher, Thomas E Mueller, Bruno Daubeuf, Hermann Wagner, Carsten J KirschningAbstract:Gram-Negative Bacterial Infection is a major cause of sepsis and septic shock. An important inducer of inflammation underlying both syndromes is the cellular recognition of Bacterial products through pattern recognition receptors (PRRs), including Toll-like receptors (TLRs). We identified a novel antagonistic mAb (named 1A6) that recognizes the extracellular portion of the TLR4–MD-2 complex. If applied to mice before Infection with clinical isolates of Salmonella enterica or Escherichia coli and subsequent antibiotic therapy, 1A6 prevented otherwise fatal shock, whereas application of 1A6 after Infection was ineffective. In contrast, coapplication of 1A6 and an anti-TLR2 mAb up to 4 h after Infection with Gram-Negative bacteria, in combination with the start of antibiotic therapy (mimicking clinical conditions), provided robust protection. Consistent with our findings in mice, dual blockade of TLR2 and TLR4 inhibited TNF-α release from human peripheral blood mononuclear cells upon Gram-Negative Bacterial Infection/antibiotic therapy. Both murine splenocytes and human PBMCs released IFN-γ in a TLR4-dependent manner, leading to enhanced surface TLR2 expression and sensitivity for TLR2 ligands. Our results implicate TLR2 as an important, TLR4-driven sensor of Gram-Negative Bacterial Infection and provide a rationale for blockade of both TLRs, in addition to antibiotic therapy for the treatment of Gram-Negative Bacterial Infection.
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lipopolysaccharide binding protein is required to combat a murine gram negative Bacterial Infection
Nature, 1997Co-Authors: Robert Smail Jack, Xiaolong Fan, Martin Bernheiden, Gabriele Rune, Monika Ehlers, Albert Weber, Gerhard Kirsch, Renate Mentel, Birgit Furll, Marina A FreudenbergAbstract:Lipopolysaccharide-binding protein is required to combat a murine Gram-Negative Bacterial Infection
Bruno Lemaitre - One of the best experts on this subject based on the ideXlab platform.
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The Drosophila inhibitor of apoptosis protein DIAP2 functions in innate immunity and is essential to resist Gram-Negative Bacterial Infection.
Molecular and Cellular Biology, 2006Co-Authors: François Leulier, Nouara Lhocine, Bruno Lemaitre, Pascal MeierAbstract:The founding member of the inhibitor of apoptosis protein (IAP) family was originally identified as a cell death inhibitor. However, recent evidence suggests that IAPs are multifunctional signaling devices that influence diverse biological processes. To investigate the in vivo function of Drosophila melanogaster IAP2, we have generated diap2 null alleles. diap2 mutant animals develop normally and are fully viable, suggesting that diap2 is dispensable for proper development. However, these animals were acutely sensitive to Infection by Gram-Negative bacteria. In Drosophila, Infection by Gram-Negative bacteria triggers the innate immune response by activating the immune deficiency (imd) signaling cascade, a NF-kappaB-dependent pathway that shares striking similarities with the pathway of mammalian tumor necrosis factor receptor 1 (TNFR1). diap2 mutant flies failed to activate NF-kappaB-mediated expression of antiBacterial peptide genes and, consequently, rapidly succumbed to Bacterial Infection. Our genetic epistasis analysis places diap2 downstream of or in parallel to imd, Dredd, Tak1, and Relish. Therefore, DIAP2 functions in the host immune response to Gram-Negative bacteria. In contrast, we find that the Drosophila TNFR-associated factor (Traf) family member Traf2 is dispensable in resistance to Gram-Negative Bacterial Infection. Taken together, our genetic data identify DIAP2 as an essential component of the Imd signaling cascade, protecting the organism from infiltrating microbes.
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in vivo rna interference analysis reveals an unexpected role for gnbp1 in the defense against gram positive Bacterial Infection in drosophila adults
Journal of Biological Chemistry, 2004Co-Authors: Sebastien Pilifloury, François Leulier, Kuniaki Takahashi, Kaoru Saigo, Emmanuel Samain, Ryu Ueda, Bruno LemaitreAbstract:The Drosophila immune system discriminates between different classes of infectious microbes and responds with pathogen-specific defense reactions via the selective activation of the Toll and the immune deficiency (Imd) signaling pathways. The Toll pathway mediates most defenses against Gram-positive bacteria and fungi, whereas the Imd pathway is required to resist Gram-Negative Bacterial Infection. Microbial recognition is achieved through peptidoglycan recognition proteins (PGRPs); Gram-positive bacteria activate the Toll pathway through a circulating PGRP (PGRP-SA), and Gram-Negative bacteria activate the Imd pathway via PGRP-LC, a putative transmembrane receptor, and PGRP-LE. Gram-Negative binding proteins (GNBPs) were originally identified in Bombyx mori for their capacity to bind various microbial compounds. Three GNBPs and two related proteins are encoded in the Drosophila genome, but their function is not known. Using inducible expression of GNBP1 double-stranded RNA, we now demonstrate that GNBP1 is required for Toll activation in response to Gram-positive Bacterial Infection; GNBP1 double-stranded RNA expression renders flies susceptible to Gram-positive Bacterial Infection and reduces the induction of the antifungal peptide encoding gene Drosomycin after Infection by Gram-positive bacteria but not after fungal Infection. This phenotype induced by GNBP1 inactivation is identical to a loss-of-function mutation in PGRP-SA, and our genetic studies suggest that GNBP1 acts upstream of the Toll ligand Spatzle. Altogether, our results demonstrate that the detection of Gram-positive bacteria in Drosophila requires two putative pattern recognition receptors, PGRP-SA and GNBP1.
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mutations in the drosophila dtak1 gene reveal a conserved function for mapkkks in the control of rel nf kappab dependent innate immune responses
Genes & Development, 2001Co-Authors: Sheila Vidal, François Leulier, Ranjiv S Khush, Phoebe Tzou, Makoto Nakamura, Bruno LemaitreAbstract:In mammals, TAK1, a MAPKKK kinase, is implicated in multiple signaling processes, including the regulation of NF-kappaB activity via the IL1-R/TLR pathways. TAK1 function has largely been studied in cultured cells, and its in vivo function is not fully understood. We have isolated null mutations in the Drosophila dTAK1 gene that encodes dTAK1, a homolog of TAK1. dTAK1 mutant flies are viable and fertile, but they do not produce antiBacterial peptides and are highly susceptible to Gram-Negative Bacterial Infection. This phenotype is similar to the phenotypes generated by mutations in components of the Drosophila Imd pathway. Our genetic studies also indicate that dTAK1 functions downstream of the Imd protein and upstream of the IKK complex in the Imd pathway that controls the Rel/NF-kappaB like transactivator Relish. In addition, our epistatic analysis places the caspase, Dredd, downstream of the IKK complex, which supports the idea that Relish is processed and activated by a caspase activity. Our genetic demonstration of dTAK1's role in the regulation of Drosophila antimicrobial peptide gene expression suggests an evolutionary conserved role for TAK1 in the activation of Rel/NF-kappaB-mediated host defense reactions.
François Leulier - One of the best experts on this subject based on the ideXlab platform.
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The Drosophila inhibitor of apoptosis protein DIAP2 functions in innate immunity and is essential to resist Gram-Negative Bacterial Infection.
Molecular and Cellular Biology, 2006Co-Authors: François Leulier, Nouara Lhocine, Bruno Lemaitre, Pascal MeierAbstract:The founding member of the inhibitor of apoptosis protein (IAP) family was originally identified as a cell death inhibitor. However, recent evidence suggests that IAPs are multifunctional signaling devices that influence diverse biological processes. To investigate the in vivo function of Drosophila melanogaster IAP2, we have generated diap2 null alleles. diap2 mutant animals develop normally and are fully viable, suggesting that diap2 is dispensable for proper development. However, these animals were acutely sensitive to Infection by Gram-Negative bacteria. In Drosophila, Infection by Gram-Negative bacteria triggers the innate immune response by activating the immune deficiency (imd) signaling cascade, a NF-kappaB-dependent pathway that shares striking similarities with the pathway of mammalian tumor necrosis factor receptor 1 (TNFR1). diap2 mutant flies failed to activate NF-kappaB-mediated expression of antiBacterial peptide genes and, consequently, rapidly succumbed to Bacterial Infection. Our genetic epistasis analysis places diap2 downstream of or in parallel to imd, Dredd, Tak1, and Relish. Therefore, DIAP2 functions in the host immune response to Gram-Negative bacteria. In contrast, we find that the Drosophila TNFR-associated factor (Traf) family member Traf2 is dispensable in resistance to Gram-Negative Bacterial Infection. Taken together, our genetic data identify DIAP2 as an essential component of the Imd signaling cascade, protecting the organism from infiltrating microbes.
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in vivo rna interference analysis reveals an unexpected role for gnbp1 in the defense against gram positive Bacterial Infection in drosophila adults
Journal of Biological Chemistry, 2004Co-Authors: Sebastien Pilifloury, François Leulier, Kuniaki Takahashi, Kaoru Saigo, Emmanuel Samain, Ryu Ueda, Bruno LemaitreAbstract:The Drosophila immune system discriminates between different classes of infectious microbes and responds with pathogen-specific defense reactions via the selective activation of the Toll and the immune deficiency (Imd) signaling pathways. The Toll pathway mediates most defenses against Gram-positive bacteria and fungi, whereas the Imd pathway is required to resist Gram-Negative Bacterial Infection. Microbial recognition is achieved through peptidoglycan recognition proteins (PGRPs); Gram-positive bacteria activate the Toll pathway through a circulating PGRP (PGRP-SA), and Gram-Negative bacteria activate the Imd pathway via PGRP-LC, a putative transmembrane receptor, and PGRP-LE. Gram-Negative binding proteins (GNBPs) were originally identified in Bombyx mori for their capacity to bind various microbial compounds. Three GNBPs and two related proteins are encoded in the Drosophila genome, but their function is not known. Using inducible expression of GNBP1 double-stranded RNA, we now demonstrate that GNBP1 is required for Toll activation in response to Gram-positive Bacterial Infection; GNBP1 double-stranded RNA expression renders flies susceptible to Gram-positive Bacterial Infection and reduces the induction of the antifungal peptide encoding gene Drosomycin after Infection by Gram-positive bacteria but not after fungal Infection. This phenotype induced by GNBP1 inactivation is identical to a loss-of-function mutation in PGRP-SA, and our genetic studies suggest that GNBP1 acts upstream of the Toll ligand Spatzle. Altogether, our results demonstrate that the detection of Gram-positive bacteria in Drosophila requires two putative pattern recognition receptors, PGRP-SA and GNBP1.
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mutations in the drosophila dtak1 gene reveal a conserved function for mapkkks in the control of rel nf kappab dependent innate immune responses
Genes & Development, 2001Co-Authors: Sheila Vidal, François Leulier, Ranjiv S Khush, Phoebe Tzou, Makoto Nakamura, Bruno LemaitreAbstract:In mammals, TAK1, a MAPKKK kinase, is implicated in multiple signaling processes, including the regulation of NF-kappaB activity via the IL1-R/TLR pathways. TAK1 function has largely been studied in cultured cells, and its in vivo function is not fully understood. We have isolated null mutations in the Drosophila dTAK1 gene that encodes dTAK1, a homolog of TAK1. dTAK1 mutant flies are viable and fertile, but they do not produce antiBacterial peptides and are highly susceptible to Gram-Negative Bacterial Infection. This phenotype is similar to the phenotypes generated by mutations in components of the Drosophila Imd pathway. Our genetic studies also indicate that dTAK1 functions downstream of the Imd protein and upstream of the IKK complex in the Imd pathway that controls the Rel/NF-kappaB like transactivator Relish. In addition, our epistatic analysis places the caspase, Dredd, downstream of the IKK complex, which supports the idea that Relish is processed and activated by a caspase activity. Our genetic demonstration of dTAK1's role in the regulation of Drosophila antimicrobial peptide gene expression suggests an evolutionary conserved role for TAK1 in the activation of Rel/NF-kappaB-mediated host defense reactions.
