The Experts below are selected from a list of 8496 Experts worldwide ranked by ideXlab platform
Gabriel Nunez - One of the best experts on this subject based on the ideXlab platform.
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tlr agonists stimulate nlrp3 dependent il 1β production independently of the Purinergic P2X7 Receptor in dendritic cells and in vivo
Journal of Immunology, 2013Co-Authors: Luigi Franchi, Gabriel NunezAbstract:On the basis of studies in mouse macrophages, activation of the nucleotide-binding oligomerization domain-like Receptor (NLR) pyrin domain-containing 3 (Nlrp3) inflammasome is thought to require two signals. The first signal is provided by TLR stimulation and triggers the synthesis of the IL-1β precursor and Nlrp3. The second signal can be mediated by stimulation of the Purinergic Receptor P2X ligand-gated ion channel 7 (P2X7) by millimolar concentrations of ATP. However, these high concentrations of ATP are not found normally in the in vivo extracellular milieu, raising concern about the physiological relevance of the ATP-P2X7 pathway of inflammasome activation. In this article, we show that unlike macrophages, murine bone marrow-derived and splenic dendritic cells (DCs) can secrete substantial amounts of mature IL-1β upon stimulation with TLR ligands in the absence of ATP stimulation. The differential ability of DCs to release IL-1β and activate caspase-1 was associated with increased expression of Nlrp3 under steady-state conditions and of pro-IL-1β and Nlrp3 after stimulation with TLR agonists. IL-1β secretion from stimulated DCs was largely dependent on the Nlrp3 inflammasome, but independent of P2X7 and unaffected by incubation with apyrase. More importantly, i.p. administration of LPS induced IL-1β production in serum, which was abrogated in Nlrp3-null mice but was unaffected in P2X7-deficient mice. These results demonstrate differential regulation of the Nlrp3 inflammasome in macrophages and DCs. Furthermore, they challenge the idea that the ATP-P2X7 axis is critical for TLR-induced IL-1β production via the Nlrp3 inflammasome in vivo.
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differential requirement of P2X7 Receptor and intracellular k for caspase 1 activation induced by intracellular and extracellular bacteria
Journal of Biological Chemistry, 2007Co-Authors: Luigi Franchi, Thirumaladevi Kanneganti, George R Dubyak, Gabriel NunezAbstract:Abstract Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that plays an important role in host defense and inflammatory diseases. The maturation and secretion of IL-1β are mediated by caspase-1, a protease that processes pro-IL-1β into biologically active IL-1β. The activity of caspase-1 is controlled by the inflammasome, a multiprotein complex formed by NLR proteins and the adaptor ASC, that induces the activation of caspase-1. The current model proposes that changes in the intracellular concentration of K+ potentiate caspase-1 activation induced by the recognition of bacterial products. However, the roles of P2X7 Receptor and intracellular K+ in IL-1β secretion induced by bacterial infection remain unknown. Here we show that, in response to Toll-like Receptor agonists such as lipopolysaccharide or infection with extracellular bacteria Staphylococcus aureus and Escherichia coli, efficient caspase-1 activation is only triggered by addition of ATP, a signal that promotes caspase-1 activation through depletion of intracellular K+ caused by stimulation of the Purinergic P2X7 Receptor. In contrast, activation of caspase-1 that relies on cytosolic sensing of flagellin or intracellular bacteria did not require ATP stimulation or depletion of cytoplasmic K+. Consistently, caspase-1 activation induced by intracellular Salmonella or Listeria was unimpaired in macrophages deficient in P2X7 Receptor. These results indicate that, unlike caspase-1 induced by Toll-like Receptor agonists and ATP, activation of the inflammasome by intracellular bacteria and cytosolic flagellin proceeds normally in the absence of P2X7 Receptor-mediated cytoplasmic K+ perturbations.
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differential requirement of P2X7 Receptor and intracellular k for caspase 1 activation induced by intracellular and extracellular bacteria
Journal of Biological Chemistry, 2007Co-Authors: Luigi Franchi, Thirumaladevi Kanneganti, George R Dubyak, Gabriel NunezAbstract:Interleukin-1beta (IL-1beta) is a pro-inflammatory cytokine that plays an important role in host defense and inflammatory diseases. The maturation and secretion of IL-1beta are mediated by caspase-1, a protease that processes pro-IL-1beta into biologically active IL-1beta. The activity of caspase-1 is controlled by the inflammasome, a multiprotein complex formed by NLR proteins and the adaptor ASC, that induces the activation of caspase-1. The current model proposes that changes in the intracellular concentration of K(+) potentiate caspase-1 activation induced by the recognition of bacterial products. However, the roles of P2X7 Receptor and intracellular K(+) in IL-1beta secretion induced by bacterial infection remain unknown. Here we show that, in response to Toll-like Receptor agonists such as lipopolysaccharide or infection with extracellular bacteria Staphylococcus aureus and Escherichia coli, efficient caspase-1 activation is only triggered by addition of ATP, a signal that promotes caspase-1 activation through depletion of intracellular K(+) caused by stimulation of the Purinergic P2X7 Receptor. In contrast, activation of caspase-1 that relies on cytosolic sensing of flagellin or intracellular bacteria did not require ATP stimulation or depletion of cytoplasmic K(+). Consistently, caspase-1 activation induced by intracellular Salmonella or Listeria was unimpaired in macrophages deficient in P2X7 Receptor. These results indicate that, unlike caspase-1 induced by Toll-like Receptor agonists and ATP, activation of the inflammasome by intracellular bacteria and cytosolic flagellin proceeds normally in the absence of P2X7 Receptor-mediated cytoplasmic K(+) perturbations.
Luigi Franchi - One of the best experts on this subject based on the ideXlab platform.
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tlr agonists stimulate nlrp3 dependent il 1β production independently of the Purinergic P2X7 Receptor in dendritic cells and in vivo
Journal of Immunology, 2013Co-Authors: Luigi Franchi, Gabriel NunezAbstract:On the basis of studies in mouse macrophages, activation of the nucleotide-binding oligomerization domain-like Receptor (NLR) pyrin domain-containing 3 (Nlrp3) inflammasome is thought to require two signals. The first signal is provided by TLR stimulation and triggers the synthesis of the IL-1β precursor and Nlrp3. The second signal can be mediated by stimulation of the Purinergic Receptor P2X ligand-gated ion channel 7 (P2X7) by millimolar concentrations of ATP. However, these high concentrations of ATP are not found normally in the in vivo extracellular milieu, raising concern about the physiological relevance of the ATP-P2X7 pathway of inflammasome activation. In this article, we show that unlike macrophages, murine bone marrow-derived and splenic dendritic cells (DCs) can secrete substantial amounts of mature IL-1β upon stimulation with TLR ligands in the absence of ATP stimulation. The differential ability of DCs to release IL-1β and activate caspase-1 was associated with increased expression of Nlrp3 under steady-state conditions and of pro-IL-1β and Nlrp3 after stimulation with TLR agonists. IL-1β secretion from stimulated DCs was largely dependent on the Nlrp3 inflammasome, but independent of P2X7 and unaffected by incubation with apyrase. More importantly, i.p. administration of LPS induced IL-1β production in serum, which was abrogated in Nlrp3-null mice but was unaffected in P2X7-deficient mice. These results demonstrate differential regulation of the Nlrp3 inflammasome in macrophages and DCs. Furthermore, they challenge the idea that the ATP-P2X7 axis is critical for TLR-induced IL-1β production via the Nlrp3 inflammasome in vivo.
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differential requirement of P2X7 Receptor and intracellular k for caspase 1 activation induced by intracellular and extracellular bacteria
Journal of Biological Chemistry, 2007Co-Authors: Luigi Franchi, Thirumaladevi Kanneganti, George R Dubyak, Gabriel NunezAbstract:Abstract Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that plays an important role in host defense and inflammatory diseases. The maturation and secretion of IL-1β are mediated by caspase-1, a protease that processes pro-IL-1β into biologically active IL-1β. The activity of caspase-1 is controlled by the inflammasome, a multiprotein complex formed by NLR proteins and the adaptor ASC, that induces the activation of caspase-1. The current model proposes that changes in the intracellular concentration of K+ potentiate caspase-1 activation induced by the recognition of bacterial products. However, the roles of P2X7 Receptor and intracellular K+ in IL-1β secretion induced by bacterial infection remain unknown. Here we show that, in response to Toll-like Receptor agonists such as lipopolysaccharide or infection with extracellular bacteria Staphylococcus aureus and Escherichia coli, efficient caspase-1 activation is only triggered by addition of ATP, a signal that promotes caspase-1 activation through depletion of intracellular K+ caused by stimulation of the Purinergic P2X7 Receptor. In contrast, activation of caspase-1 that relies on cytosolic sensing of flagellin or intracellular bacteria did not require ATP stimulation or depletion of cytoplasmic K+. Consistently, caspase-1 activation induced by intracellular Salmonella or Listeria was unimpaired in macrophages deficient in P2X7 Receptor. These results indicate that, unlike caspase-1 induced by Toll-like Receptor agonists and ATP, activation of the inflammasome by intracellular bacteria and cytosolic flagellin proceeds normally in the absence of P2X7 Receptor-mediated cytoplasmic K+ perturbations.
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differential requirement of P2X7 Receptor and intracellular k for caspase 1 activation induced by intracellular and extracellular bacteria
Journal of Biological Chemistry, 2007Co-Authors: Luigi Franchi, Thirumaladevi Kanneganti, George R Dubyak, Gabriel NunezAbstract:Interleukin-1beta (IL-1beta) is a pro-inflammatory cytokine that plays an important role in host defense and inflammatory diseases. The maturation and secretion of IL-1beta are mediated by caspase-1, a protease that processes pro-IL-1beta into biologically active IL-1beta. The activity of caspase-1 is controlled by the inflammasome, a multiprotein complex formed by NLR proteins and the adaptor ASC, that induces the activation of caspase-1. The current model proposes that changes in the intracellular concentration of K(+) potentiate caspase-1 activation induced by the recognition of bacterial products. However, the roles of P2X7 Receptor and intracellular K(+) in IL-1beta secretion induced by bacterial infection remain unknown. Here we show that, in response to Toll-like Receptor agonists such as lipopolysaccharide or infection with extracellular bacteria Staphylococcus aureus and Escherichia coli, efficient caspase-1 activation is only triggered by addition of ATP, a signal that promotes caspase-1 activation through depletion of intracellular K(+) caused by stimulation of the Purinergic P2X7 Receptor. In contrast, activation of caspase-1 that relies on cytosolic sensing of flagellin or intracellular bacteria did not require ATP stimulation or depletion of cytoplasmic K(+). Consistently, caspase-1 activation induced by intracellular Salmonella or Listeria was unimpaired in macrophages deficient in P2X7 Receptor. These results indicate that, unlike caspase-1 induced by Toll-like Receptor agonists and ATP, activation of the inflammasome by intracellular bacteria and cytosolic flagellin proceeds normally in the absence of P2X7 Receptor-mediated cytoplasmic K(+) perturbations.
Yandan Yao - One of the best experts on this subject based on the ideXlab platform.
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mir 150 promotes human breast cancer growth and malignant behavior by targeting the pro apoptotic Purinergic P2X7 Receptor
PLOS ONE, 2013Co-Authors: Songyin Huang, Yongsong Chen, Nengyong Ouyang, Jianing Chen, Xiaoqiang Liu, Ling Lin, Yandan YaoAbstract:The P2X7 Receptor regulates cell growth through mediation of apoptosis. Low level expression of P2X7 has been linked to cancer development because tumor cells harboring a defective P2X7 mechanism can escape P2X7 pro-apoptotic control. microRNAs (miRNAs) function as negative regulators of post-transcriptional gene expression, playing major roles in cellular differentiation, proliferation, and metastasis. In this study, we found that miR-150 was over-expressed in breast cancer cell lines and tissues. In these breast cancer cell lines, blocking the action of miR-150 with inhibitors leads to cell death, while ectopic expression of the miR-150 results in increased cell proliferation. We deploy a microRNA sponge strategy to inhibit miR-150 in vitro, and the result demonstrates that the 3′-untranslated region (3′UTR) of P2X7 Receptor contains a highly conserved miR-150-binding motif and its direct interaction with miR-150 down-regulates endogenous P2X7 protein levels. Furthermore, our findings demonstrate that miR-150 over-expression promotes growth, clonogenicity and reduces apoptosis in breast cancer cells. Meanwhile, these findings can be decapitated in nude mice with breast cancer xenografts. Finally, these observations strengthen our working hypothesis that up-regulation of miR-150 in breast cancer is inversely associated with P2X7 Receptor expression level. Together, these findings establish miR-150 as a novel regulator of P2X7 and a potential therapeutic target for breast cancer.
Nancy J Rothwell - One of the best experts on this subject based on the ideXlab platform.
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Purinergic P2X7 Receptor activation of microglia induces cell death via an interleukin 1 independent mechanism
Molecular and Cellular Neuroscience, 2002Co-Authors: David Brough, Rosalind Le Feuvre, Yoichiro Iwakura, Nancy J RothwellAbstract:Abstract Activation of Purinergic P2X7 Receptors, principally by extracellular ATP, promotes the processing and release of the cytokine interleukin-1β (IL-1β) and induces cell death in activated microglia and macrophages. The objective of this study was to determine if IL-1β release contributes directly to this cell death in microglia. Exposure of microglia to bacterial lipopolysaccharide (LPS) and ATP induced release of IL-1β and IL-1α, as well as cell death. Neither cell death nor IL-1 release was observed in microglia lacking the P2X7 Receptor. Microglia from mice lacking the IL-1β gene demonstrated a profile of death identical to that of wild-type microglia in response to LPS and ATP. Thus, IL-1β is not required for P2X7 Receptor-stimulated microglial death.
Lieve Moons - One of the best experts on this subject based on the ideXlab platform.
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increased P2X7 Receptor binding is associated with neuroinflammation in acute but not chronic rodent models for parkinson s disease
Frontiers in Neuroscience, 2019Co-Authors: Melissa Crabbe, Anke Van Der Perren, Ilse Bollaerts, Savannah Kounelis, Veerle Baekelandt, Guy Bormans, Cindy Casteels, Lieve MoonsAbstract:The Purinergic P2X7 Receptor is a key mediator in (neuro)inflammation, a process that is associated with neurodegeneration and excitotoxicity in Parkinson's disease (PD). Recently, P2X7 imaging has become possible with [11C]JNJ-(54173)717. We investigated P2X7 availability, in comparison with availability of the translocator protein (TSPO), in two well-characterized rat models of PD using in vitro autoradiography at multiple time points throughout the disease progression. Rats received either a unilateral injection with 6-hydroxydopamine (6-OHDA) in the striatum, or with recombinant adeno-associated viral vector overexpressing human A53T alpha-synuclein (α-SYN) in the substantia nigra. Transverse cryosections were incubated with [11C]JNJ-717 for P2X7 or [18F]DPA-714 for TSPO. [11C]JNJ-717 binding ratios were transiently elevated in the striatum of 6-OHDA rats at day 14-28 post-injection, with peak P2X7 binding at day 14. This largely coincided with the time course of striatal [18F]DPA-714 binding which was elevated at day 7-21, with peak TSPO binding at day 7. Increased P2X7 availability co-localized with microglial, but not astrocyte or neuronal markers. In the chronic α-SYN model, no significant differences were found in P2X7 binding, although in vitro TSPO overexpression was reported previously. This first study showed an increased P2X7 availability in the acute PD model in a time window corresponding with elevated TSPO binding and motor behavior changes. In contrast, the dynamics of TSPO and P2X7 were divergent in the chronic α-SYN model where no P2X7 changes were detectable. Overall, extended P2X7 phenotyping is warranted prior to implementation of P2X7 imaging for monitoring of neuroinflammation.
