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Jürg Tschopp - One of the best experts on this subject based on the ideXlab platform.
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tissues suggesting a site specific role in the inflammatory response inflammasome components nalp 1 and 3 show distinct but separate expression profiles in human
2013Co-Authors: Jürg Tschopp, Fabio Martinon, Laetitia Agostini, Alain J Kummer, Roel Broekhuizen, Helen Everett, Loes M Kuijk, Robin Van BruggenAbstract:SUMMARY Several autoinflammatory disorders such as Muckle–Wells syndrome arecharacterized by mutations in the NALP3/cryopyrin gene. NALP3 and NALP1 proteins canassemble to inflammasomes that activate caspase-1, resulting in the processing of pro-inflammatory cytokines IL-1b and IL-18. The present study was designed to determine whichcells and tissues express NALP1 and NALP3. Monoclonal antibodies were developed andtheir use revealed distinct distribution profiles of NALP1 and NALP3. Granulocytes, mono-cytes (very weakly), dendritic cells, and B and T cells all express NALP1 and NALP3. Highestlevels of NALP1 are found in T cells and Langerhans cells. Furthermore, NALP1 is present inglandular epithelial structures such as stomach, gut, lung, and, surprisingly, in neurons andtestis. In contrast to NALP1, NALP3 shows a more restricted tissue distribution with expres-sionmainlyinnon-keratinizingepitheliaintheoropharynx,esophagus,andectocervix.More-over, NALP3 expression is found in the urothelial layer in the bladder. Likewise, a differencein subcellular distribution between NALP1 and NALP3 is observed because NALP1 is local-ized mainly in the nucleus, whereas NALP3 is predominantly cytoplasmic. We propose thatthe presence of NALP3 in epithelial cells lining the oral and genital tracts allows the rapidsensing of invading pathogens, thereby triggering an innate immune response.
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cutting edge alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome
Journal of Immunology, 2008Co-Authors: Mirjam Kool, Virgine Pétrilli, Thibaut De Smedt, Aline Rolaz, Hamida Hammad, Menno Van Nimwegen, Ingrid M Bergen, Rosa Castillo, Bart N Lambrecht, Jürg TschoppAbstract:Adjuvants are vaccine additives that stimulate the immune system without having any specific antigenic effect of itself. In this study we show that alum adjuvant induces the release of IL-1beta from macrophages and dendritic cells and that this is abrogated in cells lacking various NALP3 inflammasome components. The NALP3 inflammasome is also required in vivo for the innate immune response to OVA in alum. The early production of IL-1beta and the influx of inflammatory cells into the peritoneal cavity is strongly reduced in NALP3-deficient mice. The activation of adaptive cellular immunity to OVA-alum is initiated by monocytic dendritic cell precursors that induce the expansion of Ag-specific T cells in a NALP3-dependent way. We propose that, in addition to TLR stimulators, agonists of the NALP3 inflammasome should also be considered as vaccine adjuvants.
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The inflammasome: a danger sensing complex triggering innate immunity.
Current opinion in immunology, 2007Co-Authors: Virgine Pétrilli, Catherine Dostert, Daniel A. Muruve, Jürg TschoppAbstract:The NOD-like receptors (NLR) are a family of intracellular sensors of microbial motifs and 'danger signals' that have emerged as being crucial components of the innate immune responses and inflammation. Several NLRs (NALPs and IPAF) form a caspase-1-activating multiprotein complex, termed inflammasome, that processes proinflammatory cytokines including IL-1beta. Amongst the various inflammasomes, the NALP3 inflammasome is particularly qualified to sense a plethora of diverse molecules, ranging from bacterial muramyldipeptide to monosodium urate crystals. The important role of the NALP3 inflammasome is emphasized by the identification of mutations in the NALP3 gene that are associated with a susceptibility to inflammatory disorders. These and other issues related to the inflammasome are discussed in this review.
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Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration
Cell Death & Differentiation, 2007Co-Authors: Virgine Pétrilli, Fabio Martinon, Sophie Papin, Catherine Dostert, A Mayor, Jürg TschoppAbstract:Inflammasomes are Nod-like receptor(NLR)- and caspase-1-containing cytoplasmic multiprotein complexes, which upon their assembly, process and activate the proinflammatory cytokines interleukin (IL)-1 β and IL-18. The inflammasomes harboring the NLR members NALP1, NALP3 and IPAF have been best characterized. While the IPAF inflammasome is activated by bacterial flagellin, activation of the NALP3 inflammasome is triggered not only by several microbial components, but also by a plethora of danger-associated host molecules such as uric acid. How NALP3 senses these chemically unrelated activators is not known. Here, we provide evidence that activation of NALP3, but not of the IPAF inflammasome, is blocked by inhibiting K^+ efflux from cells. Low intracellular K^+ is also a requirement for NALP1 inflammasome activation by lethal toxin of Bacillus anthracis . In vitro , NALP inflammasome assembly and caspase-1 recruitment occurs spontaneously at K^+ concentrations below 90 m M , but is prevented at higher concentrations. Thus, low intracellular K^+ may be the least common trigger of NALP-inflammasome activation.
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NALP Inflammasomes: a central role in innate immunity
Seminars in Immunopathology, 2007Co-Authors: Fabio Martinon, Olivier Gaide, Virgine Pétrilli, Annick Mayor, Jürg TschoppAbstract:Inflammasomes are cytoplasmic multiprotein complexes that mediate the maturation of the proinflammatory cytokines interleukin-1β (IL-1β), IL-18, and possibly IL-33 by controlling the activation of the inflammatory caspases-1 and -5. Assembly of inflammasomes depends on NOD-like receptor (NLR) family members such as NALPs, NAIP, and IPAF . Various microbial and endogenous stimuli activate different types of inflammasomes. This article focuses on the Pyrin domain containing NLRs, known as NALP proteins. Recent findings provide exciting insights into how these proteins might be activated and also provide evidence of the critical role of the NALP inflammasomes in innate immunity and inflammatory diseases.
Sergio Crovella - One of the best experts on this subject based on the ideXlab platform.
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hiv 1 induces NALP3 inflammasome expression and interleukin 1β secretion in dendritic cells from healthy individuals but not from hiv positive patients
AIDS, 2012Co-Authors: Alessandra Pontillo, Sergio Crovella, Lais Teodoro Da Silva, Telma Miyuki Oshiro, Claudia Finazzo, Alberto Jose Da Silva DuarteAbstract:OBJECTIVE NALP3-inflammasome is an innate mechanism, alternative to type-1 interferon, which is able to recognize nucleic acids and viruses in the cytoplasm and to induce pro-inflammatory response. Here, we hypothesized the involvement of inflammasome in the early defense against HIV-1 and in the full maturation of dendritic cells: for this, we evaluated the response of dendritic cells pulsed with HIV-1 in terms of inflammasome activation in healthy donors. Moreover, inflammasome response to HIV was evaluated in HIV-infected individuals. DESIGN AND METHODS Monocyte-derived dendritic cells isolated from 20 healthy individuals (HC-DC) and 20 HIV-1-infected patients (HIV-DC) were pulsed with alditrithiol-2-inactivated HIV-1. We then analyzed inflammasome genes expression and interleukin-1β (IL-1β) secretion. RESULTS In HC-DC, HIV-1 induced higher NLRP3/NALP3 mRNA expression compared with other inflammasome genes such as NALP1/NLRP1 or IPAF/NLRC4 (P < 0.001). This augmented expression was accompanied by CASP1-increased and IL1B-increased mRNA levels and by a significant increment of IL-1β secretion (P < 0.05). Otherwise, HIV-1 failed to activate inflammasome and cytokine production in HIV-DC. HIV-DC showed an increased NLRP3/NALP3 basal expression, suggesting a chronic inflammatory profile of patients' immune cells. CONCLUSION HIV-1 was able to induce a NALP3-inflammasome response in healthy individuals, indicating that this inflammasome could play a role in the first steps of HIV-1 infection; the consequent inflammatory process may be important for directing host immune response against the virus and/or disease progression. HIV-DC seemed to be chronically activated, but unresponsive against pathogens. Our findings could be of interest considering the ongoing research about dendritic cell manipulation and therapeutic strategies for AIDS involving dendritic cell-based immune-vaccines.
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the missense variation q705k in cias1 NALP3 nlrp3 gene and an nlrp1 haplotype are associated with celiac disease
The American Journal of Gastroenterology, 2011Co-Authors: Alessandra Pontillo, Anna Vendramin, Eulalia Catamo, Annalisa Fabris, Sergio CrovellaAbstract:OBJECTIVES: Celiac disease (CD) is a multifactorial common disorder with several susceptibility loci. Variations in the NALP1/NLRP1 and NALP3/NLRP3 genes have been reported to confer risk for several autoimmune conditions. We hypothesized that polymorphisms in these genes, due to their role in innate immunity and inflammatory processes, may affect susceptibility to CD. METHODS: Two single-nucleotide polymorphisms (SNPs) in NLRP1 (rs12150220, rs2670660) and two SNPs (rs10754558, rs35829419) in NLRP3 genes were genotyped in 504 CD Italian patients and 256 healthy controls. RESULTS: The minor A allele of NLRP3 rs35829419 (Q705K) polymorphism appeared to exert a protective role against the development of CD (P=0.029; odds ratio (OR)=0.56). Moreover, a particular NLRP1 haplotype was associated with predisposition to CD (P=0.003; OR=1.38), even more when present in combination with the rs35829419 major C allele (P=0.002; OR=1.42). CONCLUSIONS: We hypothesized that the deregulation of CIAS1/NALP3/NLRP3 and NALP1/NLRP1 inflammasomes could have a role in CD pathogenesis.
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The missense variation Q705K in CIAS1/NALP3/NLRP3 gene and an NLRP1 haplotype are associated with celiac disease.
The American Journal of Gastroenterology, 2011Co-Authors: Alessandra Pontillo, Anna Vendramin, Eulalia Catamo, Annalisa Fabris, Sergio CrovellaAbstract:OBJECTIVES: Celiac disease (CD) is a multifactorial common disorder with several susceptibility loci. Variations in the NALP1/NLRP1 and NALP3/NLRP3 genes have been reported to confer risk for several autoimmune conditions. We hypothesized that polymorphisms in these genes, due to their role in innate immunity and inflammatory processes, may affect susceptibility to CD. METHODS: Two single-nucleotide polymorphisms (SNPs) in NLRP1 (rs12150220, rs2670660) and two SNPs (rs10754558, rs35829419) in NLRP3 genes were genotyped in 504 CD Italian patients and 256 healthy controls. RESULTS: The minor A allele of NLRP3 rs35829419 (Q705K) polymorphism appeared to exert a protective role against the development of CD (P=0.029; odds ratio (OR)=0.56). Moreover, a particular NLRP1 haplotype was associated with predisposition to CD (P=0.003; OR=1.38), even more when present in combination with the rs35829419 major C allele (P=0.002; OR=1.42). CONCLUSIONS: We hypothesized that the deregulation of CIAS1/NALP3/NLRP3 and NALP1/NLRP1 inflammasomes could have a role in CD pathogenesis.
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two snps in nlrp3 gene are involved in the predisposition to type 1 diabetes and celiac disease in a pediatric population from northeast brazil
Autoimmunity, 2010Co-Authors: Alessandra Pontillo, Lucas Andre Cavalcanti Brandao, Rafael Lima Guimaraes, J. Araujo, Ludovica Segat, Sergio CrovellaAbstract:Recent findings provide evidence of the critical role of innate immunity NALP1/NLRP1 and NALP3/NLRP3/CIAS1 genes in inflammatory diseases, and also in the predisposition to autoimmune disorders.We evaluated the possible association of five single nucleotide polymorphisms (SNPs), two in NLRP1 gene and three in NLRP3 gene, in pediatric patients from the north eastern region of Brazil affected by type-1 diabetes (T1D, n = 196), celiac disease (CD, n = 59), and atopic dermatitis (AD, n = 165), and in healthy individuals (n = 192).Our results demonstrated that NLRP3 rs10754558 SNP was associated specifically to T1D (p = 4exp-3) and NLRP3 rs358294199 SNP to CD (p = 5exp-4) in the Brazilian population. Despite its strong association with T1D in Norwegian population, NLRP1 was not associated with T1D, in the Brazilian population. According to previous studies in Caucasoid cohorts, NLRP1 and NLRP3 seemed not to be associated to AD.Since it has been reported that IL-1beta has a systemic effect in the lost of the im...
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The inhibition of mevalonate pathway induces upregulation of NALP3 expression: new insight in the pathogenesis of mevalonate kinase deficiency.
European journal of human genetics : EJHG, 2010Co-Authors: Alessandra Pontillo, Elisa Paoluzzi, Sergio CrovellaAbstract:Mevalonate kinase deficiency (MKD) is a rare hereditary auto-inflammatory syndrome due to mutations in mevalonate kinase, the second enzyme of mevalonate pathway of cholesterol, and nonsterol-isoprenoids biosynthesis. The shortage of mevalonate-derived intermediates, and in particular of geranylgeranyl pyrophosphate (GGPP), has been linked with the activation of caspase-1 and thereby with the production of IL-1β, but the true concatenation of these two events has not been clarified yet. We hypothesized that inflammasomes could mediate the activation of caspase-1 due to the shortage of GGPP. We monitored the expression of the principal proteins (NALP1, NALP3 and IPAF) of the three known inflammasomes, first in a cellular model of MKD and then in two MKD patients, after bacterial lipopolysaccharide (LPS) stimulation. In healthy subjects, alendronate alone induced the expression of NALP1 and NALP3, and then together with LPS it induced a dramatic increase in NALP3 expression. In MKD patients, NALP3 expression was higher than in untreated healthy controls. Our results, although preliminary, showed that the inhibition of the mevalonate pathway led to a hyper-expression of NALP3, suggesting a possible involvement of NALP3-inflammasome in the activation of caspase-1 consequent to GGPP decrement. This is the first time that the involvement of the inflammasome complexes was shown in MKD pathogenesis.
Xiaoming Deng - One of the best experts on this subject based on the ideXlab platform.
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tim4 regulates NALP3 inflammasome expression and activity during monocyte macrophage dysfunction in septic shock patients
Burns, 2020Co-Authors: Zheng Liu, Kezhe Tan, Miaomiao Fei, Fang Chen, Xiaoming DengAbstract:Sepsis is the leading cause of death in burn patients. Monocytes/macrophages rapidly exhibit impaired production of proinflammatory cytokines and an elevated generation of anti-inflammatory cytokines in septic patients with immunosuppression. However, the expression patterns of Tim4 and Nod-like receptor protein 3 (NALP3) inflammasome and their roles during immunosuppression in septic shock patients are not well understood. Tim4 and NALP3 inflammasome expression in monocytes were downregulated in immunosuppressive patients with sepsis compared with healthy volunteers. Meanwhile, NALP3 inflammasome expression was upregulated by Tim4 overexpression in murine bone marrow-derived macrophages (BMDMs) and J774A.1 macrophages. Tim4 overexpression improved the ability of BMDMs and J774A.1 macrophages to produce proinflammatory cytokines and increased the expression of cleaved-caspase-1 (p10) after LPS/ATP stimulation. In addition, overexpression of Tim4 enhanced phagocytosis of apoptotic polymorphonuclear neutrophils (PMNs) by BMDMs and J774A.1 macrophages, while depletion of NALP3 in Tim4 overexpressing BMDMs and J774A.1 macrophages decreased phagocytosis of apoptotic PMNs. In summary, the expression of Tim4 and NALP3 inflammasome in monocytes/macrophages was downregulated in septic shock patients, and diminished expression of Tim4 and NALP3 inflammasome in monocytes/macrophages might play a critical role in sepsis-elicited immunosuppression.
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Tim4 regulates NALP3 inflammasome expression and activity during monocyte/macrophage dysfunction in septic shock patients.
Burns : journal of the International Society for Burn Injuries, 2019Co-Authors: Zheng Liu, Kezhe Tan, Miaomiao Fei, Fang Chen, Xiaoming DengAbstract:Sepsis is the leading cause of death in burn patients. Monocytes/macrophages rapidly exhibit impaired production of proinflammatory cytokines and an elevated generation of anti-inflammatory cytokines in septic patients with immunosuppression. However, the expression patterns of Tim4 and Nod-like receptor protein 3 (NALP3) inflammasome and their roles during immunosuppression in septic shock patients are not well understood. Tim4 and NALP3 inflammasome expression in monocytes were downregulated in immunosuppressive patients with sepsis compared with healthy volunteers. Meanwhile, NALP3 inflammasome expression was upregulated by Tim4 overexpression in murine bone marrow-derived macrophages (BMDMs) and J774A.1 macrophages. Tim4 overexpression improved the ability of BMDMs and J774A.1 macrophages to produce proinflammatory cytokines and increased the expression of cleaved-caspase-1 (p10) after LPS/ATP stimulation. In addition, overexpression of Tim4 enhanced phagocytosis of apoptotic polymorphonuclear neutrophils (PMNs) by BMDMs and J774A.1 macrophages, while depletion of NALP3 in Tim4 overexpressing BMDMs and J774A.1 macrophages decreased phagocytosis of apoptotic PMNs. In summary, the expression of Tim4 and NALP3 inflammasome in monocytes/macrophages was downregulated in septic shock patients, and diminished expression of Tim4 and NALP3 inflammasome in monocytes/macrophages might play a critical role in sepsis-elicited immunosuppression.
Fabio Martinon - One of the best experts on this subject based on the ideXlab platform.
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tissues suggesting a site specific role in the inflammatory response inflammasome components nalp 1 and 3 show distinct but separate expression profiles in human
2013Co-Authors: Jürg Tschopp, Fabio Martinon, Laetitia Agostini, Alain J Kummer, Roel Broekhuizen, Helen Everett, Loes M Kuijk, Robin Van BruggenAbstract:SUMMARY Several autoinflammatory disorders such as Muckle–Wells syndrome arecharacterized by mutations in the NALP3/cryopyrin gene. NALP3 and NALP1 proteins canassemble to inflammasomes that activate caspase-1, resulting in the processing of pro-inflammatory cytokines IL-1b and IL-18. The present study was designed to determine whichcells and tissues express NALP1 and NALP3. Monoclonal antibodies were developed andtheir use revealed distinct distribution profiles of NALP1 and NALP3. Granulocytes, mono-cytes (very weakly), dendritic cells, and B and T cells all express NALP1 and NALP3. Highestlevels of NALP1 are found in T cells and Langerhans cells. Furthermore, NALP1 is present inglandular epithelial structures such as stomach, gut, lung, and, surprisingly, in neurons andtestis. In contrast to NALP1, NALP3 shows a more restricted tissue distribution with expres-sionmainlyinnon-keratinizingepitheliaintheoropharynx,esophagus,andectocervix.More-over, NALP3 expression is found in the urothelial layer in the bladder. Likewise, a differencein subcellular distribution between NALP1 and NALP3 is observed because NALP1 is local-ized mainly in the nucleus, whereas NALP3 is predominantly cytoplasmic. We propose thatthe presence of NALP3 in epithelial cells lining the oral and genital tracts allows the rapidsensing of invading pathogens, thereby triggering an innate immune response.
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signaling by ros drives inflammasome activation
European Journal of Immunology, 2010Co-Authors: Fabio MartinonAbstract:Inflammasomes are innate immune signaling pathways that sense pathogens and injury to direct the proteolytic maturation of inflammatory cytokines such as IL-1beta and IL-18. Among inflammasomes, the NLRP3/NALP3 inflammasome is the most studied. However, little is known on the molecular mechanisms that mediate its assembly and activation. Recent findings suggest that ROS are produced by NLRP3/NALP3 activators and are essential secondary messengers signaling NLRP3/NALP3 inflammasome activation.
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Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration
Cell Death & Differentiation, 2007Co-Authors: Virgine Pétrilli, Fabio Martinon, Sophie Papin, Catherine Dostert, A Mayor, Jürg TschoppAbstract:Inflammasomes are Nod-like receptor(NLR)- and caspase-1-containing cytoplasmic multiprotein complexes, which upon their assembly, process and activate the proinflammatory cytokines interleukin (IL)-1 β and IL-18. The inflammasomes harboring the NLR members NALP1, NALP3 and IPAF have been best characterized. While the IPAF inflammasome is activated by bacterial flagellin, activation of the NALP3 inflammasome is triggered not only by several microbial components, but also by a plethora of danger-associated host molecules such as uric acid. How NALP3 senses these chemically unrelated activators is not known. Here, we provide evidence that activation of NALP3, but not of the IPAF inflammasome, is blocked by inhibiting K^+ efflux from cells. Low intracellular K^+ is also a requirement for NALP1 inflammasome activation by lethal toxin of Bacillus anthracis . In vitro , NALP inflammasome assembly and caspase-1 recruitment occurs spontaneously at K^+ concentrations below 90 m M , but is prevented at higher concentrations. Thus, low intracellular K^+ may be the least common trigger of NALP-inflammasome activation.
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NALP Inflammasomes: a central role in innate immunity
Seminars in Immunopathology, 2007Co-Authors: Fabio Martinon, Olivier Gaide, Virgine Pétrilli, Annick Mayor, Jürg TschoppAbstract:Inflammasomes are cytoplasmic multiprotein complexes that mediate the maturation of the proinflammatory cytokines interleukin-1β (IL-1β), IL-18, and possibly IL-33 by controlling the activation of the inflammatory caspases-1 and -5. Assembly of inflammasomes depends on NOD-like receptor (NLR) family members such as NALPs, NAIP, and IPAF . Various microbial and endogenous stimuli activate different types of inflammasomes. This article focuses on the Pyrin domain containing NLRs, known as NALP proteins. Recent findings provide exciting insights into how these proteins might be activated and also provide evidence of the critical role of the NALP inflammasomes in innate immunity and inflammatory diseases.
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activation of the il 1β processing inflammasome is involved in contact hypersensitivity
Journal of Investigative Dermatology, 2007Co-Authors: Hideki Watanabe, Fabio Martinon, Olivier Gaide, Virgine Pétrilli, Jürg Tschopp, Emmanuel Contassot, Stephanie Roques, J A Kummer, Lars E FrenchAbstract:The inflammasome is a cytosolic protein complex regulating the activation of caspase-1, which cleaves the pro-inflammatory cytokines IL-1 β and IL-18 into their active form. The inflammasome is composed of a NACHT-, LRR- and pyrin (NALP) family member that acts as a sensor for danger signals and the adaptor protein apoptosis-associated speck-like protein containing a CARD domain (ASC), which allows the recruitment of caspase-1 in the complex. In the skin, exposure to contact sensitizers (CS) such as trinitro-chlorobenzene causes an immune response called contact hypersensitivity (CHS) or eczema. In this delayed-type hypersensitivity response, efficient priming of the adaptive immunity depends on the concomitant activation of the innate immune system, including IL-1 β /IL-18 activation in the skin. To determine if the inflammasome contributes to CHS, we have analyzed its capacity to react to CS in vitro and in vivo . We show here that key components of the inflammasome are present in human keratinocytes and that CS like trinitro-chlorobenzene induce caspase-1/ASC dependent IL-1 β and IL-18 processing and secretion. We also show that ASC- and NALP3-deficient mice display an impaired response to CS. These findings suggest that CS act as danger signals that activate the inflammasome in the skin, and reveal a new role of NALP3 and ASC as regulators of innate immunity in CHS.
Lawrence W. Chamley - One of the best experts on this subject based on the ideXlab platform.
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il 1 beta but not the NALP3 inflammasome is an important determinant of endothelial cell responses to necrotic dangerous trophoblastic debris
Placenta, 2015Co-Authors: Jia Wei, Qi Chen, Joanna L. James, Peter Stone, Lawrence W. ChamleyAbstract:Abstract Introduction Necrotic but not apoptotic trophoblastic debris can induce endothelial cell activation but the mechanism by which endothelial cells distinguish apoptotic from necrotic debris is unclear. The NALP3 inflammasome is a pattern recognition receptor that macrophages employ to recognise “danger signals” in necrotic cell corpses. In this study, we hypothesized that endothelial cells can identify and respond to necrotic trophoblastic debris via the NALP3 inflammasome. Methods The effect of trophoblastic debris on endothelial expression of NALP3 inflammasome components was investigated using qRT-PCR, immunoassays and fluorescent caspase 1 activity assay. IL-1β in was quantified by ELISA. Endothelial cell activation was measured by cell surface ICAM expression and monocytes adhesion assay. Results The NALP3 inflammasome was expressed in resting vascular endothelial cells and is involved in endothelial response to danger signals. However, exposure to necrotic trophoblastic debris did not significantly alter the expression of any of the three components of the NALP3 inflammasome at the mRNA level, nor was caspase-1 activation increased. Conditioned media from endothelial cells exposed to necrotic trophoblastic debris contained elevated levels of IL-1β which was derived from the necrotic debris and which contributed to endothelial cell activation. Discussion Necrotic trophoblastic debris induced endothelial cell activation through the IL-1β/IL-1R pathway. However, the NALP3 inflammasome in endothelial cells was not involved in this process.
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IL-1 beta but not the NALP3 inflammasome is an important determinant of endothelial cell responses to necrotic/dangerous trophoblastic debris
Placenta, 2015Co-Authors: Jia Wei, Qi Chen, Joanna L. James, Peter Stone, Lawrence W. ChamleyAbstract:Abstract Introduction Necrotic but not apoptotic trophoblastic debris can induce endothelial cell activation but the mechanism by which endothelial cells distinguish apoptotic from necrotic debris is unclear. The NALP3 inflammasome is a pattern recognition receptor that macrophages employ to recognise “danger signals” in necrotic cell corpses. In this study, we hypothesized that endothelial cells can identify and respond to necrotic trophoblastic debris via the NALP3 inflammasome. Methods The effect of trophoblastic debris on endothelial expression of NALP3 inflammasome components was investigated using qRT-PCR, immunoassays and fluorescent caspase 1 activity assay. IL-1β in was quantified by ELISA. Endothelial cell activation was measured by cell surface ICAM expression and monocytes adhesion assay. Results The NALP3 inflammasome was expressed in resting vascular endothelial cells and is involved in endothelial response to danger signals. However, exposure to necrotic trophoblastic debris did not significantly alter the expression of any of the three components of the NALP3 inflammasome at the mRNA level, nor was caspase-1 activation increased. Conditioned media from endothelial cells exposed to necrotic trophoblastic debris contained elevated levels of IL-1β which was derived from the necrotic debris and which contributed to endothelial cell activation. Discussion Necrotic trophoblastic debris induced endothelial cell activation through the IL-1β/IL-1R pathway. However, the NALP3 inflammasome in endothelial cells was not involved in this process.
