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
Immunogenicity of Whole-Parasite Vaccines against Plasmodium falciparum Involves Malarial Hemozoin and Host TLR9
Cevayir Coban,Yoshikatsu Igari,Masanori Yagi,Thornik Reimer,Shohei Koyama,Taiki Aoshi,Keiichi Ohata,Toshihiro Tsukui,Fumihiko Takeshita,Kazuo Sakurai,Takahisa Ikegami,Atsushi Nakagawa,Toshihiro Horii,Gabriel Núñez,Ken Ishii,Shizuo Akira +15 more
TL;DR: HZ can influence adaptive immune responses to malaria infection and may have therapeutic value in vaccine adjuvant development, according to its method of synthesis and particle size.
Journal ArticleDOI
Proteins derived from neutrophil extracellular traps may serve as self-antigens and mediate organ damage in autoimmune diseases
TL;DR: The autoimmune diseases linked to NETosis are reviewed, with a focus on how modified proteins externalized on NETs may trigger loss of immune tolerance and promote organ damage.
Journal ArticleDOI
Lighting the fires within: the cell biology of autoinflammatory diseases
TL;DR: Recent discoveries of new links between endoplasmic reticulum stress and inflammatory signalling pathways support the emerging view that autoinflammatory diseases may be due to pathological dysregulation of stress-sensing pathways that normally function in host defence.
Journal ArticleDOI
The Concise Guide to PHARMACOLOGY 2013/14: Catalytic Receptors
Stephen P.H. Alexander,Helen E. Benson,Elena Faccenda,Adam J. Pawson,Joanna L. Sharman,Michael Spedding,John A. Peters,Anthony J. Harmar +7 more
TL;DR: The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands.
Journal ArticleDOI
Complicated Pericarditis: Understanding Risk Factors and Pathophysiology to Inform Imaging and Treatment.
Paul Cremer,Arnav Kumar,Apostolos Kontzias,Carmela D. Tan,E. Rene Rodriguez,Massimo Imazio,Allan L. Klein +6 more
TL;DR: The authors conclude that early high-dose corticosteroids, a lack of colchicine, and an elevated high-sensitivity C-reactive protein are associated with the development of complicated pericarditis.
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