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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Nod-like proteins in inflammation and disease.
TL;DR: The current knowledge on the function of these proteins in immunity and inflammation is summarized, with a focus on their participation in different disease pathologies.
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Felix Knauf,John R. Asplin,Ignacio Granja,Insa M. Schmidt,Gilbert W. Moeckel,Rachel J. David,Richard A. Flavell,Peter S. Aronson +7 more
TL;DR: Progressive renal failure in oxalate nephropathy results primarily from NALP3-mediated inflammation, thereby excluding differences in intestinal oxalates handling to explain the observed phenotype.
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TL;DR: O Ongoing inflammation in double-cytokine knockout CAPS mice implicated a role for caspase-1-mediated pyroptosis and confirmed that CAPS is inflammasome dependent, indicating that IL-1 and IL-18 drive pathology at different stages of the disease process.
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Macrophage endocytosis of high-mobility group box 1 triggers pyroptosis
Jia Xu,Yiguo Jiang,Juan Wang,Xiaolian Shi,Quan Liu,Z Liu,Yuehua Li,Melanie J. Scott,Guozhi Xiao,Shilai Li,Liyan Fan,Timothy R. Billiar,Mark Wilson,Jie Fan +13 more
TL;DR: It is demonstrated that HMGB1, acting through RAGE and dynamin-dependent signaling, initiatesHMGB1endocytosis, which in turn induces cell pyroptosis, shedding light on the regulatory role of ligand-receptor internalization in directing cell fate, which may have an important role in the progress of inflammation following infection and injury.
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Interferon-β therapy against EAE is effective only when development of the disease depends on the NLRP3 inflammasome.
Makoto Inoue,Kristi L. Williams,T Oliver,Peter Vandenabeele,Peter Vandenabeele,Jayant V. Rajan,Jayant V. Rajan,Edward A. Miao,Mari L. Shinohara +8 more
TL;DR: It is demonstrated that signaling by IFNAR on macrophages inhibits activation of Rac1 and the generation of reactive oxygen species (ROS) through suppressor of cytokine signaling 1 (SOCS1) and suppressed the activity of the Nod-like receptor family, pyrin domain–containing 3 (NLRP3) inflammasome, which resulted in attenuated EAE pathogenicity.
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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