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.
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.


CONCLUSIONS
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.
Joosten
Leo A B
LA
Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. l.joosten@aig.umcn.nl
Netea
Mihai G
MG
Mylona
Eleni
E
Koenders
Marije I
MI
Malireddi
R K Subbarao
RK
Oosting
Marije
M
Stienstra
Rinke
R
van de Veerdonk
Frank L
FL
Stalenhoef
Anton F
AF
Giamarellos-Bourboulis
Evangelos J
EJ
Kanneganti
Thirumala-Devi
TD
van der Meer
Jos W M
JW
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D015210:Arthritis, Gouty / Q000139:chemically induced / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000378:metabolism*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis*; D007719:Knee Joint / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D018709:Statistics, Nonparametric; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D014527:Uric Acid
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D005227:Fatty Acids; D053583:Interleukin-1beta; C498534:Pycard protein, mouse; D051195:Toll-Like Receptor 2; D014527:Uric Acid; D020170:Caspase 1