Gout-associated uric acid crystals activate the NALP3 inflammasome
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.
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Colchicine impairs neutrophil adhesion to vascular endothelium and degranulation and blocks activation of the NLRP3 inflammasome, which is required for cleaving caspase-1 leading to production of IL-1β and IL-18.
“Colchicine impairs neutrophil adhesion to vascular endothelium and degranulation and blocks activation of the NLRP3 (NOD-, LRR-, and pyrin domaincontaining protein 3) inflammasome, which is required for cleaving caspase-1 leading to the production of IL-1 β and IL-18. 134-136”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [135]
Uric acid can function as a DAMP by activating the inflammasome in APCs, stimulating production of IL-1β, IL-18 and IL-33 via caspase-1.
“Nucleotide products such as uric acid can also function as DAMPs, presumably by activating the inflammasome in APC, thereby stimulating the production of inflammatory cytokines such as interleukin-1β (IL-1β), IL-18 and IL-33, the secretion of which depends on the inflammasome-mediated activation of caspase-145,46.”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [46]
The amount of mature IL-1β released after asbestos exposure was similar to that seen with MSU.
“The secretion of mature IL-1β induced by asbestos was comparable to amounts observed with monosodium urate crystals (MSU), a known potent activator of IL-1β processing (7) (Fig. 1, A and B).”
From Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica (2008) · cites this paper as [7]
Nalp3 can detect endogenous danger signals, including ATP and MSU.
“In addition to PAMPs, Nalp3 has the extraordinary capacity of sensing endogenous stress-associated danger signals (DAMPs) such as ATP (9) or MSU (7).”
From Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica (2008) · cites this paper as [7]
The Nalp3 inflammasome has been linked to excessive IL-1β in autoinflammatory conditions like Muckle-Wells syndrome and in inflammatory diseases such as gout and pseudogout.
“The Nalp3 inflammasome is implicated in the pathological increase of IL-1β production in autoinflammatory syndromes, such as Muckle-Wells syndrome (22), as well as inflammatory processes, such as gout and pseudogout (7).”
From Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica (2008) · cites this paper as [7]
The NLRP3 inflammasome senses crystalline danger signals that can occur during autoinflammatory diseases and environmental diseases.
“The NLRP3 inflammasome senses crystalline danger signals that can occur during autoinflammatory diseases, such as gout or atherosclerosis, and environmental diseases, such as silicosis or asbestosis (18, 20, 22).”
From Volcanic Ash Activates the NLRP3 Inflammasome in Murine and Human Macrophages (2018) · cites this paper as [18]
Inhalation of crystalline silica can induce inflammation by stimulating the NLRP3 inflammasome.
“Inhalation of crystalline silica can induce inflammation by stimulating the NLRP3 inflammasome, a cytosolic receptor complex that plays a critical role in driving inflammatory immune responses.”
From Volcanic Ash Activates the NLRP3 Inflammasome in Murine and Human Macrophages (2018) · cites this paper as [18]
NLRP3 has been shown to respond to sterile stimuli, including asbestos, silica, MSU and CPPD crystals, cholesterol crystals and β-amyloid fibrils.
“NLRP3 has been shown to respond to sterile stimuli, including asbestos, silica, MSU and CPPD crystals55, cholesterol crystals and β-amyloid fibrils56.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [55]
Urate and cholesterol crystals, as well as sterile particulates, can bypass the requirement for ATP and P2RX7 for IL-1β production.
“Urate and cholesterol crystals, as well as sterile particulates, for example, can bypass the requirement for ATP and P2RX7 for IL-1β production55,59.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [55]
In mouse models of sterile injury, such as gout, asbestosis and silicosis, NLRP3-deficient mice exhibited decreased inflammation with reduced levels of tissue infiltration by neutrophils or macrophages.
“Consistently, in mouse models of sterile injury, such as gout, asbestosis and silicosis, NLRP3-deficient mice exhibited decreased inflammation with reduced levels of tissue infiltration by neutrophils or macrophages55,57,58.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [55]
The inflammasome is a multimolecular cytosolic sensor that detects pathogenic microorganisms and sterile stressors and activates caspase-1 during the process of pyroptosis, which, in turn, causes the inactive precursor forms of interleukin-1β and interleukin-18 to become the active forms.
“The inflammasome is a multimolecular cytosolic sensor that detects pathogenic microorganisms and sterile stressors and activates caspase-1 during the process of pyroptosis, which, in turn, causes the inactive precursor forms of interleukin-1β and interleukin-18 to become the active forms.”
From Cytokine storm (2020) · cites this paper as [41]
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- Authors
- Martinon, F., Pétrilli, V., Mayor, A., Tardivel, A., & Tschopp, J.
- Affiliations
- University of Lausanne (CH)
- Corresponding author
- Tschopp, Jürg
- Venue
- Nature
- Published
- 2006-01-11
- Volume
- 440
- Issue
- 7081
- Pages
- 237-241
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2009800174
- Cited by
- 5,326
- References
- 31
- Citations by year
- 2026: 227 · 2025: 246 · 2024: 305 · 2023: 310 · 2022: 333 · 2021: 335 · 2020: 340 · 2019: 297 · 2018: 280 · 2017: 248 · 2016: 287 · 2015: 290 · 2014: 271 · 2013: 299 · 2012: 238
- FWCI
- 76.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Nephrology › Gout, Hyperuricemia, Uric Acid
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- NLRP3 inflammasome, NLRP3, gout, urate crystals, monosodium urate, calcium pyrophosphate dihydrate, pseudogout, caspase-1, IL-1β, IL-18, autoinflammatory disease, innate immunity, crystal-induced inflammation, neutrophil influx, IL-1 receptor, macrophages
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Calcium Pyrophosphate, Carrier Proteins, Cell Line, Cells, Cultured, Chondrocalcinosis, Colchicine, Disease Models, Animal, Gout, Humans, Inflammation, Interleukin-1, Macrophages, Neutrophils, Peritonitis, Uric Acid, Receptors, Interleukin-1, Caspase 1, Mice
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