Gout-associated uric acid crystals activate the NALP3 inflammasome
TLDR
It is shown that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1β and IL-18 in mice deficient in the IL-1β receptor.Abstract:
Development of the acute and chronic inflammatory responses known as gout and pseudogout are associated with the deposition of monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals, respectively, in joints and periarticular tissues. Although MSU crystals were first identified as the aetiological agent of gout in the eighteenth century and more recently as a 'danger signal' released from dying cells, little is known about the molecular mechanisms underlying MSU- or CPPD-induced inflammation. Here we show that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1beta and IL-18. Macrophages from mice deficient in various components of the inflammasome such as caspase-1, ASC and NALP3 are defective in crystal-induced IL-1beta activation. Moreover, an impaired neutrophil influx is found in an in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or mice deficient in the IL-1beta receptor (IL-1R). These findings provide insight into the molecular processes underlying the inflammatory conditions of gout and pseudogout, and further support a pivotal role of the inflammasome in several autoinflammatory diseases.read more
Citations
More filters
Journal ArticleDOI
Identification of a Selective and Direct NLRP3 Inhibitor to Treat Inflammatory Disorders
Hua Jiang,Hongbin He,Yun Chen,Wei Huang,J.-G. Cheng,Jin Ye,Aoli Wang,Aoli Wang,Jinhui Tao,Chao Wang,Qingsong Liu,Qingsong Liu,Tengchuan Jin,Wei Jiang,Xianming Deng,Rongbin Zhou +15 more
TL;DR: Treatment with CY-09 shows remarkable therapeutic effects on mouse models of cryopyrin-associated autoinflammatory syndrome (CAPS) and type 2 diabetes and indicates that NLRP3 can be targeted in vivo to combatNLRP3-driven diseases.
Journal ArticleDOI
Molecular characteristics of immunogenic cancer cell death.
Antoine Tesniere,Theocharis Panaretakis,Theocharis Panaretakis,Theocharis Panaretakis,Oliver Kepp,Oliver Kepp,Oliver Kepp,Lionel Apetoh,Lionel Apetoh,Lionel Apetoh,François Ghiringhelli,Laurence Zitvogel,Guido Kroemer,Guido Kroemer,Guido Kroemer +14 more
TL;DR: It is anticipated that the comprehension of the mechanisms governing the immunogenicity of cell death will have a profound impact on the design of anticancer therapies.
Journal ArticleDOI
Biglycan: A danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors
Andrea Babelova,Kristin Moreth,Kristin Moreth,Wasiliki Tsalastra-Greul,Jinyang Zeng-Brouwers,Jinyang Zeng-Brouwers,Oliver Eickelberg,Marian F. Young,Peter Bruckner,Josef Pfeilschifter,Roland M. Schaefer,Hermann Josef Gröne,Liliana Schaefer +12 more
TL;DR: The results provide evidence for direct activation of the NLRP3 inflammasome by biglycan and describe a fundamental paradigm of how tissue stress or injury is monitored by innate immune receptors detecting the release of the extracellular matrix components and turning such a signal into a robust inflammatory response.
Journal ArticleDOI
Inflammasome activation and function in liver disease
Gyongyi Szabo,Jan Petrasek +1 more
TL;DR: This Review focuses on the triggers of inflammasome activation in alcoholic steatohepatitis and NASH, chronic HCV infection, ischaemia–reperfusion injury and paracetamol-induced liver injury and proposes novel approaches in the treatment of inflammation in liver disease.
Journal ArticleDOI
Severe acute respiratory syndrome coronavirus envelope protein ion channel activity promotes virus fitness and pathogenesis.
Jose L. Nieto-Torres,Marta L. DeDiego,Carmina Verdiá-Báguena,Jose M. Jimenez-Guardeño,Jose Angel Regla-Nava,Raúl Fernandez-Delgado,Carlos Castaño-Rodríguez,Antonio Alcaraz,Jaume Torres,Vicente M. Aguilella,Luis Enjuanes +10 more
TL;DR: E protein IC activity represents a new determinant for SARS-CoV virulence, and is associated with reduced edema accumulation, the major determinant of acute respiratory distress syndrome (ARDS) leading to death.
References
More filters
Journal ArticleDOI
Innate Immune Recognition
TL;DR: Microbial recognition by Toll-like receptors helps to direct adaptive immune responses to antigens derived from microbial pathogens to distinguish infectious nonself from noninfectious self.
Journal ArticleDOI
The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.
TL;DR: In this article, the inflammasome is identified as a caspase-activating complex that comprises caspases-1, casp-5, Pycard/Asc, and NALP1, a Pyrin domain-containing protein sharing structural homology with NODs.
Journal ArticleDOI
The Danger Model: A Renewed Sense of Self
TL;DR: A model of immunity based on the idea that the immune system is more concerned with entities that do damage than with those that are foreign is outlined.
Journal ArticleDOI
Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf.
Sanjeev Mariathasan,Kim Newton,Denise M. Monack,Domagoj Vucic,Dorothy French,Wyne P. Lee,Meron Roose-Girma,Sharon Erickson,Vishva M. Dixit +8 more
TL;DR: Interestingly, cell death triggered by stimuli that engage caspase-1 was ablated in macrophages lacking either ASC or Ipaf, suggesting a coupling between the inflammatory and cell death pathways.
Journal ArticleDOI
Molecular identification of a danger signal that alerts the immune system to dying cells
TL;DR: Uric acid stimulates dendritic cell maturation and, when co-injected with antigen in vivo, significantly enhances the generation of responses from CD8+ T cells, and have important implications for vaccines, autoimmunity and inflammation.
Related Papers (5)
The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.
NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals
Peter Duewell,Hajime Kono,Katey J. Rayner,Katey J. Rayner,Cherilyn M. Sirois,Gregory I. Vladimer,Franz Bauernfeind,George S. Abela,Luigi Franchi,Guillermo Gabriel Nuñez,Max Schnurr,Terje Espevik,Egil Lien,Katherine A. Fitzgerald,Kenneth L. Rock,Kathryn J. Moore,Kathryn J. Moore,Samuel D. Wright,Veit Hornung,Eicke Latz,Eicke Latz +20 more