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
More filters
Journal ArticleDOI
Immunity and inflammation in diabetic kidney disease: translating mechanisms to biomarkers and treatment targets
Raimund Pichler,Maryam Afkarian,Brad P. Dieter,Brad P. Dieter,Katherine R. Tuttle,Katherine R. Tuttle +5 more
TL;DR: The involvement of the immune system in DKD is reviewed and important roles of key immune and inflammatory mediators are identified and one of the most recently identified biomarkers is serum amyloid A, which appears to be relatively specific for DKD.
Journal ArticleDOI
Caspase-4 is required for activation of inflammasomes.
Gabriel Sollberger,Gerhard E. Strittmatter,Magdalena Kistowska,Lars E. French,Hans-Dietmar Beer +4 more
TL;DR: It is shown that caspase-4 expression is required for UVB-induced activation of proIL-1β and for unconventional protein secretion by skin-derived keratinocytes and represents a novel target for the treatment of (auto)inflammatory diseases.
Journal ArticleDOI
Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease
TL;DR: There is a pipeline of compounds that can interfere with the inflammasome-IL-1α/IL-β- IL-1R system, ranging from recently described small molecule inhibitors of NLRP3, a component of the infammasome complex, to regulatory agency-approved IL- 1-neutralizing biologic drugs.
Journal ArticleDOI
Autoimmunity vs autoinflammation in Behcet's disease: do we oversimplify a complex disorder?
TL;DR: This review aims to make an in-depth critical analysis of current data for recent controversies on the role of innate immune system vs autoimmunity in BD.
Journal ArticleDOI
Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet-induced adipose tissue inflammation
Hiroe Honda,Yoshinori Nagai,Takayuki Matsunaga,Naoki Okamoto,Yasuharu Watanabe,Koichi Tsuneyama,Hiroaki Hayashi,Isao Fujii,Masashi Ikutani,Yoshikatsu Hirai,Atsushi Muraguchi,Kiyoshi Takatsu +11 more
TL;DR: It is shown that ILG potently inhibits the activation of NLRP3 inflammasome, and the effect is independent of its inhibitory potency on TLR4.
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.
Related Papers (5)
The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.
NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals
Peter Duewell,Hajime Kono,Katey J. Rayner,Katey J. Rayner,Cherilyn M. Sirois,Gregory I. Vladimer,Franz Bauernfeind,George S. Abela,Luigi Franchi,Guillermo Gabriel Nuñez,Max Schnurr,Terje Espevik,Egil Lien,Katherine A. Fitzgerald,Kenneth L. Rock,Kathryn J. Moore,Kathryn J. Moore,Samuel D. Wright,Veit Hornung,Eicke Latz,Eicke Latz +20 more