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 receptors: role in innate immunity and inflammatory disease.
TL;DR: The NOD-like receptors are a specialized group of intracellular receptors that represent a key component of the host innate immune system and their ability to regulate nuclear factor-kappa B signaling, interleukin-1-beta production, and cell death indicates that they are crucial to the pathogenesis of a variety of inflammatory human diseases.
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Novel role of PKR in inflammasome activation and HMGB1 release
Ben Lu,Takahisa Nakamura,Karen Inouye,Jianhua Li,Yiting Tang,Peter Lundbäck,Sergio I. Valdés-Ferrer,Peder S. Olofsson,Thomas Kalb,Jesse Roth,Yongrui Zou,Helena Erlandsson-Harris,Huan Yang,Jenny P.-Y. Ting,Haichao Wang,Ulf Andersson,Daniel J. Antoine,Sangeeta S. Chavan,Gökhan S. Hotamisligil,Kevin J. Tracey +19 more
TL;DR: Results show a crucial role for PKR in inflammasome activation, and indicate that it should be possible to pharmacologically target this molecule to treat inflammation.
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A clinical perspective of IL-1β as the gatekeeper of inflammation
TL;DR: Evidence for the involvement of IL‐1β and the clinical results of reducing IL‐ 1β activity in this broad spectrum of inflammatory diseases are the focus of this review.
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The inflammasome: a danger sensing complex triggering innate immunity.
TL;DR: The important role of the NalP3 inflammasome is emphasized by the identification of mutations in the NALP3 gene that are associated with a susceptibility to inflammatory disorders.
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The Intracellular Sensor NLRP3 Mediates Key Innate and Healing Responses to Influenza A Virus via the Regulation of Caspase-1
Paul G. Thomas,Pradyot Dash,Jerry R. Aldridge,Ali H. Ellebedy,Cory Reynolds,Amy J. Funk,William J. Martin,Mohamed Lamkanfi,Richard J. Webby,Kelli L. Boyd,Peter C. Doherty,Peter C. Doherty,Thirumala-Devi Kanneganti +12 more
TL;DR: It is demonstrated that Nlrp3 and Casp1(-/-) mice were more susceptible than wild-type mice after infection with a pathogenic influenza A virus, and cryopyrin and caspase-1 are central to both innate immunity and to moderating lung pathology in influenza pneumonia.
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