Gout and Nucleic Acid Metabolism Vol.33 No

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1 Gout and Nucleic Acid Metabolism Vol.33 No in vitro 14 IgM 1 IgM IgM 1 PAMPs Pattern recognition receptors PRRs PRRs PRRs PAMPs Toll Toll-like receptor TLR PAMPs Nod Nod-like receptor NLR RIG- I RIG-I-like receptor RLR PRRs 1 1 IL-1 IL-18 TNF- IL-6 IL-8 IL-1 IL-18 IL-1 IL-18 Hiroko Tsutsui Tetsuya Yamamoto Kenji Nakanishi

2 2 Inflammasome Caspase-1 Caspase-1 IL-1 IL-18 2 IL-1 IL-1R MyD88 3 IL-1R MyD88 IL-1 IL TLR LPS TLR4 TLR2 4 TLR2 4 TLR MyD88 NF- B TNF- IL-6 IL TREM-1 5 TREM-1 TREM TREM-1 2 Nalp3 IL-1 IL-18 Caspase-1 IL-1 IL-18 ASC Caspase-1 IL-1 IL-18 2 Caspase-1 IL-1 IL-18 PRRs Nalp3 Caspase-1 Caspase-1 IL-1 IL-18 6 Nalp3 TLRs PAMPs leucine-rich repeats (LRRs) NACHT Pyrin 7 Nalp3 NACHT 7 Nalp3 Pyrin Caspase-1 ASC Pyrin ASC CARD Caspase-1 CARD Nalp3 7 Caspase-1 Caspase-1 Caspase-1 IL- 1 IL-18 IL-1 IL-18 Caspase-1 NLR Nalp3 inflammasome Nalp3 Inflammasome B Nalp3 Caspase-1 IL-1 IL-18 8 Silica Asbestos Nalp3 inflammasome 8-10

3 Gout and Nucleic Acid Metabolism Vol.33 No Nalp3 3 ROS Nalp3 0.5 m 10 m Nalp3 B D Nalp3 Caspase-1 IL-1 IL LRRs Nalp3 Nalp3 Caspase Nalp3

4 4 NADPH oxidase Reactive oxygen species ROS NADPH oxidase Caspase-1 ROS Caspase K + K + 8 K + Nalp3 NACHT K + ROS Nalp3 Nalp3 inflammasome TLR4 11 TLR4 MyD88 TRIF TLR4 Nalp3 K + ROS 13,14 Th2 Nalp3 inflammasome Nalp3 inflammasome PLG Th2 Th2 Nalp3 inflammasome 15 Th2 4 Th2 Nalp3 Th2 Th2 HSA Th2 HSA IgG1 Nalp3 inflammasome Nalp3 ASC Caspase-1 Th2 HSA HSA IgG1 Th1 HSA IgG2a 12 Th2 Nalp3 inflammasome 3 TLR4 Nalp3

5 Gout and Nucleic Acid Metabolism Vol.33 No IL-1 IL-18 IL-1 TNF- IL PRRs Defencin Heat shock protein HMGB-1 PRRs Dangerassociated molecular patterns DAMPs DAPMs PRRs 4 Nalp3 Th2 Kanevets U Sharma K Dresser K et al A role of IgM antibodies in monosodium urate crystal formation and associated adjuvanticity J Immunol Inokuchi T Moriwaki T Tsutsui H et al Plasma interleukin IL -18 interferongamma-inducing factor and other inflammatory cytokines in patients with gouty arthritis and monosodium urate monohydrate crystal-induced secretion of IL-18 Cytokine Chen C-J Shi Y Hearn A et al MyD88- dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals J Clin Inves Liu-Bryan R Scott P Sydlaske A et al Innate Immunity conferred by Toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation Arthritis Rheum Murakami Y Akahoshi T Hayashi I et al Induction of triggering receptor expressed on myelid cells 1 in murine residential peritoneal macrophages by monosodium urate monohydrate crystals Arthritis Rheum Martinon F V Mayor A et al Goutassociated uric acid crystals activate the NALP3 inflammasome Nature Martinon F Mayor A Tschopp J The inflammasomes Guardians of the body Annu Rev Immunol Hornung V Bauernfeind F Halle A et al Silica crystals and aluminum salts activate the Nalp3 inflammasome through phagosomal destabilization Nat Immunol 9: Dostert C V Van Bruggen R et al Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science

6 Cassel S Eisenbarth SC Iyer SS et al The Nalp3 inflammasome is essential for the development of silicosis Proc Natl Acad Sci USA Imamura M Tsutsui H Yasuda K et al Contribution of TIR domain-containing adapter inducing IFN- -mediated IL-18 release to LPSinduced liver injury in mice J Hepatol In Press Eisenbarth SC Colegio OR O'Connor Jr W et al Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants Nature Kool M V De SmedtT et al Alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome J Immunol Franchi L, N ez G The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL- 1b secretion but dispensable for adjuvant activity Eur J Immunol Sharp FA Ruane D Class B et al Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome Proc Natl Acad Sci USA