The Experts below are selected from a list of 4803 Experts worldwide ranked by ideXlab platform
Hal M Hoffman - One of the best experts on this subject based on the ideXlab platform.
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Cryopyrin-Associated Periodic Syndromes (CAPS)
Textbook of Autoinflammation, 2019Co-Authors: Hal M Hoffman, Jasmin B. Kuemmerle-deschner, Raphaela Goldbach-manskyAbstract:The Cryopyrin-associated periodic syndromes (CAPS) include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID) with shared and unique clinical features. Most patients possess heterozygous NLRP3 mutations leading to a hyperactive inflammasome, subsequent overproduction of interleukin (IL)-1β and inflammatory symptoms. Diagnostic challenges include a heterogeneous multi-systemic clinical presentation, somatic mosaicism, and low penetrance mutations. IL-1 targeted therapy has become the standard of care for CAPS based on its clinical efficacy and safety.
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PW03-009 – Genetics of PFAPA syndrome
Pediatric Rheumatology, 2013Co-Authors: Lori Broderick, Daniela Carvalho, Anthony E. Magit, Wen Jiang, Shelby C. Leuin, Marcella Bothwell, Donald B. Kearns, Seth M. Pransky, Hal M HoffmanAbstract:Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome is an autoinflammatory disorder of childhood and little is known about the underlying etiology. While mutations involving the IL-1 pathway have been identified in other recurrent fever disorders, including TNF-receptor associated periodic syndrome (TRAPS) and Cryopyrin-associated periodic syndrome (CAPS), PFAPA syndrome is not traditionally considered to be a hereditary fever disorder.
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pw03 009 genetics of pfapa syndrome
Pediatric Rheumatology, 2013Co-Authors: Lori Broderick, Hal M Hoffman, Daniela Carvalho, Anthony E. Magit, Wen Jiang, Shelby C. Leuin, Marcella Bothwell, Donald B. Kearns, Seth M. PranskyAbstract:Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome is an autoinflammatory disorder of childhood and little is known about the underlying etiology. While mutations involving the IL-1 pathway have been identified in other recurrent fever disorders, including TNF-receptor associated periodic syndrome (TRAPS) and Cryopyrin-associated periodic syndrome (CAPS), PFAPA syndrome is not traditionally considered to be a hereditary fever disorder.
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role of the leucine rich repeat domain of Cryopyrin nalp3 in monosodium urate crystal induced inflammation in mice
Arthritis & Rheumatism, 2010Co-Authors: Hal M Hoffman, James L Mueller, Peter A. Scott, Amir Misaghi, Sean Stevens, George D. Yancopoulos, Andrew J. Murphy, David M. Valenzuela, Ru LiubryanAbstract:Objective The mechanism by which monosodium urate monohydrate (MSU) crystals intracellularly activate the Cryopyrin inflammasome is unknown. The aim of this study was to use a mouse molecular genetics–based approach to test whether the leucine-rich repeat (LRR) domain of Cryopyrin is required for MSU crystal–induced inflammation. Methods Cryopyrin-knockout lacZ (Cryo−Z/−Z) mice and mice with the Cryopyrin LRR domain deleted and fused to the lacZ reporter (CryoΔLRR Z/ΔLRR Z) were generated using bacterial artificial chromosome–based targeting vectors, which allow for large genomic deletions. Bone marrow–derived macrophages from CryoΔLRR Z/ΔLRR Z mice, Cryo−Z/−Z mice, and congenic wild-type (WT) mice were challenged with endotoxin-free MSU crystals under serum-free conditions. Phagocytosis and cytokine expression were assessed by flow cytometry and enzyme-linked immunosorbent assay. MSU crystals also were injected into mouse synovial-like subcutaneous air pouches. The in vivo inflammatory responses were examined. Results Release of interleukin-1β (IL-1β), but not CXCL1 and tumor necrosis factor α, was impaired in CryoΔLRR Z/ΔLRR Z and Cryo−Z/−Z mouse bone marrow–derived macrophages compared with WT mouse bone marrow–derived macrophages in response to not only MSU crystals but also other known stimuli that activate the Cryopyrin inflammasome. In addition, a comparable percentage of MSU crystals taken up by each type of bone marrow–derived macrophage was observed. Moreover, total leukocyte infiltration in the air pouch and IL-1β production were attenuated in Cryo−Z/−Z and CryoΔLRR Z/ΔLRR Z mice at 6 hours postinjection of MSU crystals compared with WT mice. Conclusion MSU crystal–induced inflammatory responses were comparably attenuated both in vitro and in vivo in CryoΔLRR Z/ΔLRR Z and Cryo−Z/−Z mice. Hence, the LRR domain of Cryopyrin plays a role in mediating MSU crystal–induced inflammation in this model.
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Role of the leucine-rich repeat domain of Cryopyrin/NALP3 in monosodium urate crystal-induced inflammation in mice.
Arthritis and rheumatism, 2010Co-Authors: Hal M Hoffman, James L Mueller, Peter A. Scott, Amir Misaghi, Sean Stevens, George D. Yancopoulos, Andrew J. Murphy, David M. Valenzuela, Ru Liu-bryanAbstract:Objective The mechanism by which monosodium urate monohydrate (MSU) crystals intracellularly activate the Cryopyrin inflammasome is unknown. The aim of this study was to use a mouse molecular genetics–based approach to test whether the leucine-rich repeat (LRR) domain of Cryopyrin is required for MSU crystal–induced inflammation. Methods Cryopyrin-knockout lacZ (Cryo−Z/−Z) mice and mice with the Cryopyrin LRR domain deleted and fused to the lacZ reporter (CryoΔLRR Z/ΔLRR Z) were generated using bacterial artificial chromosome–based targeting vectors, which allow for large genomic deletions. Bone marrow–derived macrophages from CryoΔLRR Z/ΔLRR Z mice, Cryo−Z/−Z mice, and congenic wild-type (WT) mice were challenged with endotoxin-free MSU crystals under serum-free conditions. Phagocytosis and cytokine expression were assessed by flow cytometry and enzyme-linked immunosorbent assay. MSU crystals also were injected into mouse synovial-like subcutaneous air pouches. The in vivo inflammatory responses were examined. Results Release of interleukin-1β (IL-1β), but not CXCL1 and tumor necrosis factor α, was impaired in CryoΔLRR Z/ΔLRR Z and Cryo−Z/−Z mouse bone marrow–derived macrophages compared with WT mouse bone marrow–derived macrophages in response to not only MSU crystals but also other known stimuli that activate the Cryopyrin inflammasome. In addition, a comparable percentage of MSU crystals taken up by each type of bone marrow–derived macrophage was observed. Moreover, total leukocyte infiltration in the air pouch and IL-1β production were attenuated in Cryo−Z/−Z and CryoΔLRR Z/ΔLRR Z mice at 6 hours postinjection of MSU crystals compared with WT mice. Conclusion MSU crystal–induced inflammatory responses were comparably attenuated both in vitro and in vivo in CryoΔLRR Z/ΔLRR Z and Cryo−Z/−Z mice. Hence, the LRR domain of Cryopyrin plays a role in mediating MSU crystal–induced inflammation in this model.
Thirumala-devi Kanneganti - One of the best experts on this subject based on the ideXlab platform.
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Fungal zymosan and mannan activate the Cryopyrin inflammasome
Journal of Biological Chemistry, 2009Co-Authors: Mohamed Lamkanfi, Rks Malireddi, Thirumala-devi KannegantiAbstract:Some fungal species are opportunistic pathogens that can cause infection in people with compromised immune systems. Activation of caspase-1 and the subsequent secretion of mature interleukin (IL)-1β is a major signaling pathway of the innate immune system, but how yeasts induce caspase-1 activation is unknown. We show here that stimulation of macrophages and dendritic cells with heat-killed Saccharomyces cerevisiae or the purified cell wall components zymosan and mannan induced caspase-1 activation and IL-1β secretion when combined with ATP. Macrophages deficient for the inflammasome adaptor ASC were defective in caspase-1 activation and IL-1β secretion, suggesting involvement of an ASC-dependent inflammasome. Indeed, caspase-1 activation was abrogated in macrophages lacking the NOD-like (NLR) protein Cryopyrin/Nalp3 and in wild type macrophages pretreated with the pannexin-1 inhibitor probenecid. IL-1β secretion further required the Toll-like receptor (TLR) adaptors MyD88 and TRIF, and partially relied on TLR2. We previously showed that bacterial molecules such as lipopolysaccharide (LPS) and peptidoglycan induce activation of caspase-7 through the Cryopyrin inflammasome. Similarly, Cryopyrin and ASC were required for activation of caspase-7 in macrophages stimulated with zymosan or mannan and ATP. These results demonstrate that the conserved fungal components zymosan and mannan require ASC and Cryopyrin for caspase-1 activation and IL-1β secretion and suggest an important role for the Cryopyrin inflammasome during fungal infections.
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Pannexin-1-mediated recognition of bacterial molecules activates the Cryopyrin inflammasome independent of Toll-like receptor signaling.
Immunity, 2007Co-Authors: Thirumala-devi Kanneganti, Mohamed Lamkanfi, Yun Gi Kim, Grace Y. Chen, Jong Hwan Park, Luigi Franchi, Peter Vandenabeele, Gabriel NunezAbstract:Cryopyrin is essential for caspase-1 activation triggered by Toll-like receptor (TLR) ligands in the presence of adenosine triphosphate (ATP). However, the events linking bacterial products and ATP to Cryopyrin remain unclear. Here we demonstrate that Cryopyrin-mediated caspase-1 activation proceeds independently of TLR signaling, thus dissociating caspase-1 activation and IL-1beta secretion. Instead, caspase-1 activation required pannexin-1, a hemichannel protein that interacts with the P2X(7) receptor. Direct cytosolic delivery of multiple bacterial products including lipopolysaccharide, but not flagellin, induced caspase-1 activation via Cryopyrin in the absence of pannexin-1 activity or ATP stimulation. However, unlike Ipaf-dependent caspase-1 activation, stimulation of the pannexin-1-Cryopyrin pathway by several intracellular bacteria was independent of a functional bacterial type III secretion system. These results provide evidence for cytosolic delivery and sensing of bacterial molecules as a unifying model for caspase-1 activation and position pannexin-1 as a mechanistic link between bacterial stimuli and the Cryopyrin inflammasome.
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critical role for Cryopyrin nalp3 in activation of caspase 1 in response to viral infection and double stranded rna
Journal of Biological Chemistry, 2006Co-Authors: Thirumala-devi Kanneganti, Jong Hwan Park, Luigi Franchi, Amal O. Amer, Joel Whitfield, Mathilde Bodymalapel, Zenobia F. Taraporewala, David Miller, John T. Patton, Naohiro InoharaAbstract:Viral infection induces the production of interleukin (IL)-1beta and IL-18 in macrophages through the activation of caspase-1, but the mechanism by which host cells sense viruses to induce caspase-1 activation is unknown. In this report, we have identified a signaling pathway leading to caspase-1 activation that is induced by double-stranded RNA (dsRNA) and viral infection that is mediated by Cryopyrin/Nalp3. Stimulation of macrophages with dsRNA, viral RNA, or its analog poly(I:C) induced the secretion of IL-1beta and IL-18 in a Cryopyrin-dependent manner. Consistently, caspase-1 activation triggered by poly(I:C), dsRNA, and viral RNA was abrogated in macrophages lacking Cryopyrin or the adaptor ASC (apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain) but proceeded normally in macrophages deficient in Toll-like receptor 3 or 7. We have also shown that infection with Sendai and influenza viruses activates the Cryopyrin inflammasome. Finally, Cryopyrin was required for IL-1beta production in response to poly(I:C) in vivo. These results identify a mechanism mediated by Cryopyrin and ASC that links dsRNA and viral infection to caspase-1 activation resulting in IL-1beta and IL-18 production.
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Critical Role for Cryopyrin/Nalp3 in Activation of Caspase-1 in Response to Viral Infection and Double-stranded RNA
Journal of Biological Chemistry, 2006Co-Authors: Thirumala-devi Kanneganti, Jong Hwan Park, Luigi Franchi, Mathilde Body-malapel, Amal O. Amer, Joel Whitfield, Zenobia F. Taraporewala, David Miller, John T. Patton, Naohiro InoharaAbstract:Viral infection induces the production of interleukin (IL)-1beta and IL-18 in macrophages through the activation of caspase-1, but the mechanism by which host cells sense viruses to induce caspase-1 activation is unknown. In this report, we have identified a signaling pathway leading to caspase-1 activation that is induced by double-stranded RNA (dsRNA) and viral infection that is mediated by Cryopyrin/Nalp3. Stimulation of macrophages with dsRNA, viral RNA, or its analog poly(I:C) induced the secretion of IL-1beta and IL-18 in a Cryopyrin-dependent manner. Consistently, caspase-1 activation triggered by poly(I:C), dsRNA, and viral RNA was abrogated in macrophages lacking Cryopyrin or the adaptor ASC (apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain) but proceeded normally in macrophages deficient in Toll-like receptor 3 or 7. We have also shown that infection with Sendai and influenza viruses activates the Cryopyrin inflammasome. Finally, Cryopyrin was required for IL-1beta production in response to poly(I:C) in vivo. These results identify a mechanism mediated by Cryopyrin and ASC that links dsRNA and viral infection to caspase-1 activation resulting in IL-1beta and IL-18 production.
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bacterial rna and small antiviral compounds activate caspase 1 through Cryopyrin nalp3
Nature, 2006Co-Authors: Thirumala-devi Kanneganti, Jong Hwan Park, Luigi Franchi, Nesrin Özören, Amal O. Amer, Joel Whitfield, Winfried Barchet, Marco Colonna, Mathilde Bodymalapel, Peter VandenabeeleAbstract:Missense mutations in the CIAS1 gene cause three autoinflammatory disorders: familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multiple-system inflammatory disease. Cryopyrin (also called Nalp3), the product of CIAS1, is a member of the NOD-LRR protein family that has been linked to the activation of intracellular host defence signalling pathways. Cryopyrin forms a multi-protein complex termed 'the inflammasome', which contains the apoptosis-associated speck-like protein (ASC) and caspase-1, and promotes caspase-1 activation and processing of pro-interleukin (IL)-1beta (ref. 4). Here we show the effect of Cryopyrin deficiency on inflammasome function and immune responses. Cryopyrin and ASC are essential for caspase-1 activation and IL-1beta and IL-18 production in response to bacterial RNA and the imidazoquinoline compounds R837 and R848. In contrast, secretion of tumour-necrosis factor-alpha and IL-6, as well as activation of NF-kappaB and mitogen-activated protein kinases (MAPKs) were unaffected by Cryopyrin deficiency. Furthermore, we show that Toll-like receptors and Cryopyrin control the secretion of IL-1beta and IL-18 through different intracellular pathways. These results reveal a critical role for Cryopyrin in host defence through bacterial RNA-mediated activation of caspase-1, and provide insights regarding the pathogenesis of autoinflammatory syndromes.
Gabriel Nunez - One of the best experts on this subject based on the ideXlab platform.
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pannexin 1 mediated intracellular delivery of muramyl dipeptide induces caspase 1 activation via Cryopyrin nlrp3 independently of nod2
Journal of Immunology, 2008Co-Authors: Noemi Marinagarcia, Christine Mcdonald, Luigi Franchi, Douglas Miller, Geertjan Boons, Gabriel NunezAbstract:Muramyl dipeptide (MDP), the microbial activator of nucleotide-binding oligomerization domain 2 (Nod2), induces NF-κB and MAPK activation, leading to the production of multiple anti-bacterial and proinflammatory molecules. In addition, MDP has been implicated in IL-1β secretion through the regulation of caspase-1. However, the mechanisms that mediate caspase-1 activation and IL-1β secretion in response to MDP stimulation remain poorly understood. We show here that fluorescent MDP molecules are internalized in primary macrophages and accumulate in granular structures that colocalize with markers of acidified endosomal compartments. The uptake of MDP was Nod2-independent. Upon ATP stimulation, labeled MDP was rapidly released from acidified vesicles into the cytosol, a process that required functional pannexin-1. Caspase-1 activation induced by MDP and ATP required pannexin-1 and Cryopyrin but was independent of Nod2. Conversely, induction of pro-IL-1β mRNA by MDP stimulation was abolished in Nod2-deficient macrophages but unimpaired in macrophages lacking Cryopyrin. These studies demonstrate a Nod2-independent mechanism mediated through pore-forming pannexin-1 that is required for intracellular delivery of MDP to the cytosol and caspase-1 activation. Furthermore, the work provides evidence for distinct roles of Nod2 and Cryopyrin in the regulation of MDP-induced caspase-1 activation and IL-1β secretion.
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Pannexin-1-Mediated Intracellular Delivery of Muramyl Dipeptide Induces Caspase-1 Activation via Cryopyrin/NLRP3 Independently of Nod2
The Journal of Immunology, 2008Co-Authors: Noemí Marina-garcía, Christine Mcdonald, Yun Gi Kim, Luigi Franchi, Douglas Miller, Geertjan Boons, Gabriel NunezAbstract:Muramyl dipeptide (MDP), the microbial activator of nucleotide-binding oligomerization domain 2 (Nod2), induces NF-κB and MAPK activation, leading to the production of multiple anti-bacterial and proinflammatory molecules. In addition, MDP has been implicated in IL-1β secretion through the regulation of caspase-1. However, the mechanisms that mediate caspase-1 activation and IL-1β secretion in response to MDP stimulation remain poorly understood. We show here that fluorescent MDP molecules are internalized in primary macrophages and accumulate in granular structures that colocalize with markers of acidified endosomal compartments. The uptake of MDP was Nod2-independent. Upon ATP stimulation, labeled MDP was rapidly released from acidified vesicles into the cytosol, a process that required functional pannexin-1. Caspase-1 activation induced by MDP and ATP required pannexin-1 and Cryopyrin but was independent of Nod2. Conversely, induction of pro-IL-1β mRNA by MDP stimulation was abolished in Nod2-deficient macrophages but unimpaired in macrophages lacking Cryopyrin. These studies demonstrate a Nod2-independent mechanism mediated through pore-forming pannexin-1 that is required for intracellular delivery of MDP to the cytosol and caspase-1 activation. Furthermore, the work provides evidence for distinct roles of Nod2 and Cryopyrin in the regulation of MDP-induced caspase-1 activation and IL-1β secretion.
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Pannexin-1-mediated recognition of bacterial molecules activates the Cryopyrin inflammasome independent of Toll-like receptor signaling.
Immunity, 2007Co-Authors: Thirumala-devi Kanneganti, Mohamed Lamkanfi, Yun Gi Kim, Grace Y. Chen, Jong Hwan Park, Luigi Franchi, Peter Vandenabeele, Gabriel NunezAbstract:Cryopyrin is essential for caspase-1 activation triggered by Toll-like receptor (TLR) ligands in the presence of adenosine triphosphate (ATP). However, the events linking bacterial products and ATP to Cryopyrin remain unclear. Here we demonstrate that Cryopyrin-mediated caspase-1 activation proceeds independently of TLR signaling, thus dissociating caspase-1 activation and IL-1beta secretion. Instead, caspase-1 activation required pannexin-1, a hemichannel protein that interacts with the P2X(7) receptor. Direct cytosolic delivery of multiple bacterial products including lipopolysaccharide, but not flagellin, induced caspase-1 activation via Cryopyrin in the absence of pannexin-1 activity or ATP stimulation. However, unlike Ipaf-dependent caspase-1 activation, stimulation of the pannexin-1-Cryopyrin pathway by several intracellular bacteria was independent of a functional bacterial type III secretion system. These results provide evidence for cytosolic delivery and sensing of bacterial molecules as a unifying model for caspase-1 activation and position pannexin-1 as a mechanistic link between bacterial stimuli and the Cryopyrin inflammasome.
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nod lrr proteins role in host microbial interactions and inflammatory disease
Annual Review of Biochemistry, 2005Co-Authors: Naohiro Inohara, Mathias Chamaillard, Christine Mcdonald, Gabriel NunezAbstract:▪ Abstract Nods are cytosolic proteins that contain a nucleotide-binding oligomerization domain (NOD). These proteins include key regulators of apoptosis and pathogen resistance in mammals and plants. A large number of Nods contain leucine-rich repeats (LRRs), hence referred to as NOD-LRR proteins. Genetic variation in several NOD-LRR proteins, including human Nod2, Cryopyrin, and CIITA, as well as mouse Naip5, is associated with inflammatory disease or increased susceptibility to microbial infections. Nod1, Nod2, Cryopyrin, and Ipaf have been implicated in protective immune responses against pathogens. Together with Toll-like receptors, Nod1 and Nod2 appear to play important roles in innate and acquired immunity as sensors of bacterial components. Specifically, Nod1 and Nod2 participate in the signaling events triggered by host recognition of specific motifs in bacterial peptidoglycan and, upon activation, induce the production of proinflammatory mediators. Naip5 is involved in host resistance to Legione...
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Cryopyrin-induced Interleukin 1β Secretion in Monocytic Cells ENHANCED ACTIVITY OF DISEASE-ASSOCIATED MUTANTS AND REQUIREMENT FOR ASC
Journal of Biological Chemistry, 2004Co-Authors: Theresa A Dowds, Naohiro Inohara, Junya Masumoto, Li Zhu, Gabriel NunezAbstract:Abstract Several autoinflammatory disorders are associated with missense mutations within the nucleotide-binding oligomerization domain of Cryopyrin. The mechanism by which Cryopyrin mutations cause inflammatory disease remains elusive. To understand the molecular bases of these diseases, we generated constructs to express three common Cryopyrin disease-associated mutations, R260W, D303N, and E637G, and compared their activity with that of the wild-type protein. All Cryopyrin mutant proteins tested were found to induce potent NF-κB activity when compared with the wild-type protein. This activation was dependent on the expression of ASC, an adaptor protein previously suggested to mediate Cryopyrin signaling. When the disease-associated mutants were expressed in monocytic THP-1 cells (which express endogenous ASC), each induced spontaneous IL-1β secretion, whereas wild-type protein did not. In the absence of stimuli, wild-type Cryopyrin was unable to bind to ASC, whereas the three mutants coimmunoprecipitated with ASC, suggesting a mechanism involved in the constitutive activation of mutant proteins. The induction of Cryopyrin activity by enforced oligomerization in THP-1 cells resulted in ASC binding and the secretion of IL-1β, an effect that was abolished by the inhibition of ASC expression with small interfering RNAs. Thus, Cryopyrin-mediated IL-1β secretion requires ASC in monocytic cells. Further, these results indicate that Cryopyrin disease-associated mutants are constitutively active and able to induce NF-κB activation and IL-1β secretion at least in part by an increased ability to interact with ASC.
Naohiro Inohara - One of the best experts on this subject based on the ideXlab platform.
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critical role for Cryopyrin nalp3 in activation of caspase 1 in response to viral infection and double stranded rna
Journal of Biological Chemistry, 2006Co-Authors: Thirumala-devi Kanneganti, Jong Hwan Park, Luigi Franchi, Amal O. Amer, Joel Whitfield, Mathilde Bodymalapel, Zenobia F. Taraporewala, David Miller, John T. Patton, Naohiro InoharaAbstract:Viral infection induces the production of interleukin (IL)-1beta and IL-18 in macrophages through the activation of caspase-1, but the mechanism by which host cells sense viruses to induce caspase-1 activation is unknown. In this report, we have identified a signaling pathway leading to caspase-1 activation that is induced by double-stranded RNA (dsRNA) and viral infection that is mediated by Cryopyrin/Nalp3. Stimulation of macrophages with dsRNA, viral RNA, or its analog poly(I:C) induced the secretion of IL-1beta and IL-18 in a Cryopyrin-dependent manner. Consistently, caspase-1 activation triggered by poly(I:C), dsRNA, and viral RNA was abrogated in macrophages lacking Cryopyrin or the adaptor ASC (apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain) but proceeded normally in macrophages deficient in Toll-like receptor 3 or 7. We have also shown that infection with Sendai and influenza viruses activates the Cryopyrin inflammasome. Finally, Cryopyrin was required for IL-1beta production in response to poly(I:C) in vivo. These results identify a mechanism mediated by Cryopyrin and ASC that links dsRNA and viral infection to caspase-1 activation resulting in IL-1beta and IL-18 production.
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Critical Role for Cryopyrin/Nalp3 in Activation of Caspase-1 in Response to Viral Infection and Double-stranded RNA
Journal of Biological Chemistry, 2006Co-Authors: Thirumala-devi Kanneganti, Jong Hwan Park, Luigi Franchi, Mathilde Body-malapel, Amal O. Amer, Joel Whitfield, Zenobia F. Taraporewala, David Miller, John T. Patton, Naohiro InoharaAbstract:Viral infection induces the production of interleukin (IL)-1beta and IL-18 in macrophages through the activation of caspase-1, but the mechanism by which host cells sense viruses to induce caspase-1 activation is unknown. In this report, we have identified a signaling pathway leading to caspase-1 activation that is induced by double-stranded RNA (dsRNA) and viral infection that is mediated by Cryopyrin/Nalp3. Stimulation of macrophages with dsRNA, viral RNA, or its analog poly(I:C) induced the secretion of IL-1beta and IL-18 in a Cryopyrin-dependent manner. Consistently, caspase-1 activation triggered by poly(I:C), dsRNA, and viral RNA was abrogated in macrophages lacking Cryopyrin or the adaptor ASC (apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain) but proceeded normally in macrophages deficient in Toll-like receptor 3 or 7. We have also shown that infection with Sendai and influenza viruses activates the Cryopyrin inflammasome. Finally, Cryopyrin was required for IL-1beta production in response to poly(I:C) in vivo. These results identify a mechanism mediated by Cryopyrin and ASC that links dsRNA and viral infection to caspase-1 activation resulting in IL-1beta and IL-18 production.
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nod lrr proteins role in host microbial interactions and inflammatory disease
Annual Review of Biochemistry, 2005Co-Authors: Naohiro Inohara, Mathias Chamaillard, Christine Mcdonald, Gabriel NunezAbstract:▪ Abstract Nods are cytosolic proteins that contain a nucleotide-binding oligomerization domain (NOD). These proteins include key regulators of apoptosis and pathogen resistance in mammals and plants. A large number of Nods contain leucine-rich repeats (LRRs), hence referred to as NOD-LRR proteins. Genetic variation in several NOD-LRR proteins, including human Nod2, Cryopyrin, and CIITA, as well as mouse Naip5, is associated with inflammatory disease or increased susceptibility to microbial infections. Nod1, Nod2, Cryopyrin, and Ipaf have been implicated in protective immune responses against pathogens. Together with Toll-like receptors, Nod1 and Nod2 appear to play important roles in innate and acquired immunity as sensors of bacterial components. Specifically, Nod1 and Nod2 participate in the signaling events triggered by host recognition of specific motifs in bacterial peptidoglycan and, upon activation, induce the production of proinflammatory mediators. Naip5 is involved in host resistance to Legione...
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Cryopyrin-induced Interleukin 1β Secretion in Monocytic Cells ENHANCED ACTIVITY OF DISEASE-ASSOCIATED MUTANTS AND REQUIREMENT FOR ASC
Journal of Biological Chemistry, 2004Co-Authors: Theresa A Dowds, Naohiro Inohara, Junya Masumoto, Li Zhu, Gabriel NunezAbstract:Abstract Several autoinflammatory disorders are associated with missense mutations within the nucleotide-binding oligomerization domain of Cryopyrin. The mechanism by which Cryopyrin mutations cause inflammatory disease remains elusive. To understand the molecular bases of these diseases, we generated constructs to express three common Cryopyrin disease-associated mutations, R260W, D303N, and E637G, and compared their activity with that of the wild-type protein. All Cryopyrin mutant proteins tested were found to induce potent NF-κB activity when compared with the wild-type protein. This activation was dependent on the expression of ASC, an adaptor protein previously suggested to mediate Cryopyrin signaling. When the disease-associated mutants were expressed in monocytic THP-1 cells (which express endogenous ASC), each induced spontaneous IL-1β secretion, whereas wild-type protein did not. In the absence of stimuli, wild-type Cryopyrin was unable to bind to ASC, whereas the three mutants coimmunoprecipitated with ASC, suggesting a mechanism involved in the constitutive activation of mutant proteins. The induction of Cryopyrin activity by enforced oligomerization in THP-1 cells resulted in ASC binding and the secretion of IL-1β, an effect that was abolished by the inhibition of ASC expression with small interfering RNAs. Thus, Cryopyrin-mediated IL-1β secretion requires ASC in monocytic cells. Further, these results indicate that Cryopyrin disease-associated mutants are constitutively active and able to induce NF-κB activation and IL-1β secretion at least in part by an increased ability to interact with ASC.
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Cryopyrin-induced Interleukin 1β Secretion in Monocytic Cells ENHANCED ACTIVITY OF DISEASE-ASSOCIATED MUTANTS AND REQUIREMENT FOR ASC
The Journal of biological chemistry, 2004Co-Authors: Theresa A Dowds, Naohiro Inohara, Junya Masumoto, Li Zhu, Gabriel NunezAbstract:Several autoinflammatory disorders are associated with missense mutations within the nucleotide-binding oligomerization domain of Cryopyrin. The mechanism by which Cryopyrin mutations cause inflammatory disease remains elusive. To understand the molecular bases of these diseases, we generated constructs to express three common Cryopyrin disease-associated mutations, R260W, D303N, and E637G, and compared their activity with that of the wild-type protein. All Cryopyrin mutant proteins tested were found to induce potent NF-kappaB activity when compared with the wild-type protein. This activation was dependent on the expression of ASC, an adaptor protein previously suggested to mediate Cryopyrin signaling. When the disease-associated mutants were expressed in monocytic THP-1 cells (which express endogenous ASC), each induced spontaneous IL-1beta secretion, whereas wild-type protein did not. In the absence of stimuli, wild-type Cryopyrin was unable to bind to ASC, whereas the three mutants coimmunoprecipitated with ASC, suggesting a mechanism involved in the constitutive activation of mutant proteins. The induction of Cryopyrin activity by enforced oligomerization in THP-1 cells resulted in ASC binding and the secretion of IL-1beta, an effect that was abolished by the inhibition of ASC expression with small interfering RNAs. Thus, Cryopyrin-mediated IL-1beta secretion requires ASC in monocytic cells. Further, these results indicate that Cryopyrin disease-associated mutants are constitutively active and able to induce NF-kappaB activation and IL-1beta secretion at least in part by an increased ability to interact with ASC.
Luigi Franchi - One of the best experts on this subject based on the ideXlab platform.
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pannexin 1 mediated intracellular delivery of muramyl dipeptide induces caspase 1 activation via Cryopyrin nlrp3 independently of nod2
Journal of Immunology, 2008Co-Authors: Noemi Marinagarcia, Christine Mcdonald, Luigi Franchi, Douglas Miller, Geertjan Boons, Gabriel NunezAbstract:Muramyl dipeptide (MDP), the microbial activator of nucleotide-binding oligomerization domain 2 (Nod2), induces NF-κB and MAPK activation, leading to the production of multiple anti-bacterial and proinflammatory molecules. In addition, MDP has been implicated in IL-1β secretion through the regulation of caspase-1. However, the mechanisms that mediate caspase-1 activation and IL-1β secretion in response to MDP stimulation remain poorly understood. We show here that fluorescent MDP molecules are internalized in primary macrophages and accumulate in granular structures that colocalize with markers of acidified endosomal compartments. The uptake of MDP was Nod2-independent. Upon ATP stimulation, labeled MDP was rapidly released from acidified vesicles into the cytosol, a process that required functional pannexin-1. Caspase-1 activation induced by MDP and ATP required pannexin-1 and Cryopyrin but was independent of Nod2. Conversely, induction of pro-IL-1β mRNA by MDP stimulation was abolished in Nod2-deficient macrophages but unimpaired in macrophages lacking Cryopyrin. These studies demonstrate a Nod2-independent mechanism mediated through pore-forming pannexin-1 that is required for intracellular delivery of MDP to the cytosol and caspase-1 activation. Furthermore, the work provides evidence for distinct roles of Nod2 and Cryopyrin in the regulation of MDP-induced caspase-1 activation and IL-1β secretion.
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Pannexin-1-Mediated Intracellular Delivery of Muramyl Dipeptide Induces Caspase-1 Activation via Cryopyrin/NLRP3 Independently of Nod2
The Journal of Immunology, 2008Co-Authors: Noemí Marina-garcía, Christine Mcdonald, Yun Gi Kim, Luigi Franchi, Douglas Miller, Geertjan Boons, Gabriel NunezAbstract:Muramyl dipeptide (MDP), the microbial activator of nucleotide-binding oligomerization domain 2 (Nod2), induces NF-κB and MAPK activation, leading to the production of multiple anti-bacterial and proinflammatory molecules. In addition, MDP has been implicated in IL-1β secretion through the regulation of caspase-1. However, the mechanisms that mediate caspase-1 activation and IL-1β secretion in response to MDP stimulation remain poorly understood. We show here that fluorescent MDP molecules are internalized in primary macrophages and accumulate in granular structures that colocalize with markers of acidified endosomal compartments. The uptake of MDP was Nod2-independent. Upon ATP stimulation, labeled MDP was rapidly released from acidified vesicles into the cytosol, a process that required functional pannexin-1. Caspase-1 activation induced by MDP and ATP required pannexin-1 and Cryopyrin but was independent of Nod2. Conversely, induction of pro-IL-1β mRNA by MDP stimulation was abolished in Nod2-deficient macrophages but unimpaired in macrophages lacking Cryopyrin. These studies demonstrate a Nod2-independent mechanism mediated through pore-forming pannexin-1 that is required for intracellular delivery of MDP to the cytosol and caspase-1 activation. Furthermore, the work provides evidence for distinct roles of Nod2 and Cryopyrin in the regulation of MDP-induced caspase-1 activation and IL-1β secretion.
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Pannexin-1-mediated recognition of bacterial molecules activates the Cryopyrin inflammasome independent of Toll-like receptor signaling.
Immunity, 2007Co-Authors: Thirumala-devi Kanneganti, Mohamed Lamkanfi, Yun Gi Kim, Grace Y. Chen, Jong Hwan Park, Luigi Franchi, Peter Vandenabeele, Gabriel NunezAbstract:Cryopyrin is essential for caspase-1 activation triggered by Toll-like receptor (TLR) ligands in the presence of adenosine triphosphate (ATP). However, the events linking bacterial products and ATP to Cryopyrin remain unclear. Here we demonstrate that Cryopyrin-mediated caspase-1 activation proceeds independently of TLR signaling, thus dissociating caspase-1 activation and IL-1beta secretion. Instead, caspase-1 activation required pannexin-1, a hemichannel protein that interacts with the P2X(7) receptor. Direct cytosolic delivery of multiple bacterial products including lipopolysaccharide, but not flagellin, induced caspase-1 activation via Cryopyrin in the absence of pannexin-1 activity or ATP stimulation. However, unlike Ipaf-dependent caspase-1 activation, stimulation of the pannexin-1-Cryopyrin pathway by several intracellular bacteria was independent of a functional bacterial type III secretion system. These results provide evidence for cytosolic delivery and sensing of bacterial molecules as a unifying model for caspase-1 activation and position pannexin-1 as a mechanistic link between bacterial stimuli and the Cryopyrin inflammasome.
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critical role for Cryopyrin nalp3 in activation of caspase 1 in response to viral infection and double stranded rna
Journal of Biological Chemistry, 2006Co-Authors: Thirumala-devi Kanneganti, Jong Hwan Park, Luigi Franchi, Amal O. Amer, Joel Whitfield, Mathilde Bodymalapel, Zenobia F. Taraporewala, David Miller, John T. Patton, Naohiro InoharaAbstract:Viral infection induces the production of interleukin (IL)-1beta and IL-18 in macrophages through the activation of caspase-1, but the mechanism by which host cells sense viruses to induce caspase-1 activation is unknown. In this report, we have identified a signaling pathway leading to caspase-1 activation that is induced by double-stranded RNA (dsRNA) and viral infection that is mediated by Cryopyrin/Nalp3. Stimulation of macrophages with dsRNA, viral RNA, or its analog poly(I:C) induced the secretion of IL-1beta and IL-18 in a Cryopyrin-dependent manner. Consistently, caspase-1 activation triggered by poly(I:C), dsRNA, and viral RNA was abrogated in macrophages lacking Cryopyrin or the adaptor ASC (apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain) but proceeded normally in macrophages deficient in Toll-like receptor 3 or 7. We have also shown that infection with Sendai and influenza viruses activates the Cryopyrin inflammasome. Finally, Cryopyrin was required for IL-1beta production in response to poly(I:C) in vivo. These results identify a mechanism mediated by Cryopyrin and ASC that links dsRNA and viral infection to caspase-1 activation resulting in IL-1beta and IL-18 production.
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Critical Role for Cryopyrin/Nalp3 in Activation of Caspase-1 in Response to Viral Infection and Double-stranded RNA
Journal of Biological Chemistry, 2006Co-Authors: Thirumala-devi Kanneganti, Jong Hwan Park, Luigi Franchi, Mathilde Body-malapel, Amal O. Amer, Joel Whitfield, Zenobia F. Taraporewala, David Miller, John T. Patton, Naohiro InoharaAbstract:Viral infection induces the production of interleukin (IL)-1beta and IL-18 in macrophages through the activation of caspase-1, but the mechanism by which host cells sense viruses to induce caspase-1 activation is unknown. In this report, we have identified a signaling pathway leading to caspase-1 activation that is induced by double-stranded RNA (dsRNA) and viral infection that is mediated by Cryopyrin/Nalp3. Stimulation of macrophages with dsRNA, viral RNA, or its analog poly(I:C) induced the secretion of IL-1beta and IL-18 in a Cryopyrin-dependent manner. Consistently, caspase-1 activation triggered by poly(I:C), dsRNA, and viral RNA was abrogated in macrophages lacking Cryopyrin or the adaptor ASC (apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain) but proceeded normally in macrophages deficient in Toll-like receptor 3 or 7. We have also shown that infection with Sendai and influenza viruses activates the Cryopyrin inflammasome. Finally, Cryopyrin was required for IL-1beta production in response to poly(I:C) in vivo. These results identify a mechanism mediated by Cryopyrin and ASC that links dsRNA and viral infection to caspase-1 activation resulting in IL-1beta and IL-18 production.