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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The NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation
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IKKα negatively regulates ASC-dependent inflammasome activation
Bradley N. Martin,Bradley N. Martin,Chenhui Wang,Jami Willette-Brown,Tomasz Herjan,Muhammet F. Gulen,Hao Zhou,Katarzyna Bulek,Luigi Franchi,Takashi Sato,Emad S. Alnemri,Goutham Narla,Xiao-Ping Zhong,James W. Thomas,Dennis M. Klinman,Katherine A. Fitzgerald,Michael Karin,Gabriel Núñez,George R. Dubyak,Yinling Hu,Xiaoxia Li +20 more
TL;DR: Findings reveal a IKKi-IKKα-ASC axis that serves as a common regulatory mechanism for ASC-dependent inflammasome assembly.
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The controversial relationship between NLRP3, alum, danger signals and the next‐generation adjuvants
Roberto Spreafico,Paola Ricciardi-Castagnoli,Paola Ricciardi-Castagnoli,Alessandra Mortellaro +3 more
TL;DR: Alum has been the only adjuvant licensed for human vaccines for decades and is still widely used, but its mechanism of action remains obscure, and researchers are testing adjuvants harnessing both the infectious/non‐infectious‐discriminating TLR and the danger‐sensing NLRP3 inflammasome pathways.
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The Pyroptotic Cell Death Effector Gasdermin D Is Activated by Gout-Associated Uric Acid Crystals but Is Dispensable for Cell Death and IL-1β Release.
Maryam Rashidi,Daniel S Simpson,Daniel S Simpson,Anne Hempel,Daniel Frank,Daniel Frank,Emma J. Petrie,Emma J. Petrie,Angelina J. Vince,Angelina J. Vince,Rebecca Feltham,Rebecca Feltham,Jane Murphy,Jane Murphy,Simon M Chatfield,Simon M Chatfield,Guy S. Salvesen,James M. Murphy,James M. Murphy,Ian P. Wicks,Ian P. Wicks,James E Vince +21 more
TL;DR: It is demonstrated that not all IL-1β–driven autoinflammatory conditions will benefit from the therapeutic targeting of GSDMD, and a unique mechanism of MSU crystal–induced macrophage cell death not rescued by pan-cathepsin inhibition is documented.
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