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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Uric acid as a danger signal in gout and its comorbidities
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Franz Bauernfeind,Andrea Ablasser,Eva Bartok,Sarah Kim,Jonathan L. Schmid-Burgk,Taner Cavlar,Veit Hornung +6 more
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Pattern recognition receptors and central nervous system repair.
Kristina A. Kigerl,Juan Pablo de Rivero Vaccari,W. Dalton Dietrich,Phillip G. Popovich,Robert W. Keane +4 more
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When Signaling Pathways Collide: Positive and Negative Regulation of Toll-like Receptor Signal Transduction
TL;DR: These recent findings emphasize the importance of considering TLR signaling in the context of other signaling pathways, as is likely to occur in vivo during infection and inflammation.
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An Unexpected Role for Uric Acid as an Inducer of T Helper 2 Cell Immunity to Inhaled Antigens and Inflammatory Mediator of Allergic Asthma
Mirjam Kool,Monique Willart,Menno van Nimwegen,Ingrid M. Bergen,Philippe Pouliot,J. Christian Virchow,Neil C. Rogers,Fabiola Osorio,Caetano Reis e Sousa,Hamida Hammad,Bart N. Lambrecht,Bart N. Lambrecht +11 more
TL;DR: It is shown that UA is released in the airways of allergen-challenged asthmatic patients and mice, where it was necessary for mounting T helper 2 (Th2) cell immunity, airway eosinophilia, and bronchial hyperreactivity to inhaled harmless proteins and clinically relevant house dust mite allerGEN.
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