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
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Cathepsin B Is Required for NLRP3 Inflammasome Activation in Macrophages, Through NLRP3 Interaction
Angélique Chevriaux,Thomas Pilot,Valentin Derangère,Harmonie Simonin,Pierre Martine,Fanny Chalmin,François Ghiringhelli,Cédric Rébé +7 more
TL;DR: It is shown that Cathepsin B is required for caspase-1 activation, IL-1β production and ASC speck formation, upon treatment with different types of NLRP3 activators, i.e., ATP, nigericin or crystals.
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Cellular Pyrin Domain-Only Protein 2 Is a Candidate Regulator of Inflammasome Activation
Andrea Dorfleutner,Nicole B. Bryan,Siera Jo Talbott,Kristin N. Funya,Stephanie L. Rellick,John C. Reed,Xianglin Shi,Yon Rojanasakul,Daniel C. Flynn,Christian Stehlik +9 more
TL;DR: The identification and characterization of a second cellular POP (cPOP2), which shows highest homology to the PYD of PAN1, is described, which suggests that POPs might be a common regulatory mechanism to “fine-tune” the activity of specific PYD-NLR family protein-containing inflammasomes.
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Inflammasome components Asc and caspase-1 mediate biomaterial-induced inflammation and foreign body response
Ahsan F. Malik,Rafaz Hoque,Xinshou Ouyang,Ayaz Ghani,Enping Hong,Khadija Khan,Laura Beth Moore,Gilbert Ng,Fay Munro,Richard A. Flavell,Yan Shi,Themis R. Kyriakides,Wajahat Z. Mehal +12 more
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Oliver Kepp,Michaela Semeraro,José Manuel Bravo-San Pedro,Norma Bloy,Aitziber Buqué,Xing Huang,Heng Zhou,Laura Senovilla,Guido Kroemer,Lorenzo Galluzzi +9 more
TL;DR: The role of the ER stress response in ICD and the potential value of eIF2α phosphorylation as a biomarker for this clinically relevant variant of apoptosis are discussed.
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.
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