Document Detail


Engagement of fatty acids with Toll-like receptor 2 drives interleukin-1β production via the ASC/caspase 1 pathway in monosodium urate monohydrate crystal-induced gouty arthritis.
MedLine Citation:
PMID:  20662061     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: The concept that intraarticular crystals of uric acid by themselves trigger episodes of painful gouty arthritis is inconsistent with the clinical reality. Patients with large deposits of monosodium urate monohydrate (MSU) crystals (tophi) do not necessarily experience gouty attacks. In fact, it is the excessive consumption of food or alcohol that elicits the inflammation of the acute gout attack. The aim of this study was to identify the precise mechanism that initiates flares of gouty arthritis.
METHODS: Human peripheral blood mononuclear cells (PBMCs) and murine macrophages were stimulated in vitro with MSU, free fatty acids (FFAs), or both in combination. Thereafter, production of interleukin-1β (IL-1β) and activation of caspase 1 were determined. Gouty arthritis was induced in mice with deficiencies in the genes for caspase 1, ASC, NALP3, or IL-1β, and the lack of inflammasome activity during joint swelling or other joint pathologic features was investigated in these mice.
RESULTS: MSU crystals had no biologic effects on PBMCs from healthy subjects, whereas the FFA C18:0 in the presence of MSU crystals induced the release of large amounts of IL-1β following engagement of Toll-like receptor 2 (TLR-2). Interaction of FFAs, but not alcohol, with TLR-2 synergized with MSU crystals to induce an inflammatory reaction. An important event of MSU/FFA-induced acute joint inflammation is the activation of the inflammasome. MSU/FFA-induced release of IL-1β was dependent on activation of caspase 1 and ASC, but surprisingly, not NALP3.
CONCLUSION: The synergistic effect between FFAs and MSU crystals leads to ASC/caspase 1-driven IL-1β release. This mechanism could explain how constitutionally derived metabolic events initiate attacks of gout via the induction of IL-1β-mediated joint inflammation.
Authors:
Leo A B Joosten; Mihai G Netea; Eleni Mylona; Marije I Koenders; R K Subbarao Malireddi; Marije Oosting; Rinke Stienstra; Frank L van de Veerdonk; Anton F Stalenhoef; Evangelos J Giamarellos-Bourboulis; Thirumala-Devi Kanneganti; Jos W M van der Meer
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Arthritis and rheumatism     Volume:  62     ISSN:  1529-0131     ISO Abbreviation:  Arthritis Rheum.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-02     Completed Date:  2010-11-30     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  0370605     Medline TA:  Arthritis Rheum     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3237-48     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2010 by the American College of Rheumatology.
Affiliation:
Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. l.joosten@aig.umcn.nl
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MeSH Terms
Descriptor/Qualifier:
Animals
Arthritis, Gouty / chemically induced,  metabolism*
Caspase 1 / metabolism*
Cells, Cultured
Cytoskeletal Proteins / metabolism*
Enzyme-Linked Immunosorbent Assay
Fatty Acids / metabolism*
Humans
Inflammation / metabolism
Interleukin-1beta / biosynthesis*
Knee Joint / metabolism
Leukocytes, Mononuclear / metabolism
Macrophages / metabolism
Male
Mice
Mice, Inbred C57BL
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Statistics, Nonparametric
Toll-Like Receptor 2 / metabolism*
Uric Acid
Grant Support
ID/Acronym/Agency:
AR-056296/AR/NIAMS NIH HHS; R01 AR056296/AR/NIAMS NIH HHS; R01 AR056296-02/AR/NIAMS NIH HHS; R01 AR056296-02S2/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Cytoskeletal Proteins; 0/Fatty Acids; 0/Interleukin-1beta; 0/Pycard protein, mouse; 0/Toll-Like Receptor 2; 69-93-2/Uric Acid; EC 3.4.22.36/Caspase 1
Comments/Corrections
Comment In:
Arthritis Rheum. 2010 Nov;62(11):3140-4   [PMID:  20662058 ]

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