The role of the NLRP3 inflammasome in gout

Sarah R Kingsbury, Philip G Conaghan, Michael F McDermott, Sarah R Kingsbury, Philip G Conaghan, Michael F McDermott

Abstract

Gout is an inflammatory arthritis characterized by abrupt self-limiting attacks of inflammation caused by precipitation of monosodium urate crystals (MSU) in the joint. Recent studies suggest that orchestration of the MSU-induced inflammatory response is dependent on the proinflammatory cytokine IL-1β, underlined by promising results in early IL-1 inhibitor trials in gout patients. This IL-1-dependent innate inflammatory phenotype, which is observed in a number of diseases in addition to gout, is now understood to rely on the formation of the macromolecular NLRP3 inflammasome complex in response to the MSU 'danger signal'. This review focuses on our current understanding of the NLRP3 inflammasome and its critical role in MSU-crystal induced inflammatory gout attacks. It also discusses the management of treatment-resistant acute and chronic tophaceous gout with IL-1 inhibitors; early clinical studies of rilonacept (IL-1 Trap), canakinumab (monoclonal anti-IL-1β antibody), and anakinra have all demonstrated treatment efficacy in such patients.

Keywords: IL-1; NLRP3; gout; inflammasome.

Figures

Figure 1
Figure 1
The NLRP3 inflammasome complex. The NLRP3 inflammasome complex is formed through homotypic interactions between the CARD and PYD domains of NLRP3, Pyrin, and ASC. An additional adaptor protein Cardinal is also required to facilitate activation of procaspase-1, which in turn cleaves proIL-1β to IL-1β. Abbreviations: ASC, apoptosis-associated speck-like protein; bZIP, basic leucine zipper domain; CARD, caspase activation and recruitment; CC, coiled-coil domain; FIIND, domain with a function to find; IL, interleukin; LRR, leucine-rich repeat; NACHT, domain present in neuronal apoptosis inhibitor protein (NAIP) major histocompatibility complex class II transactivator; NLRP3, NACHT domain, LRR domain, and Pyrin domain-containing protein; PYD, Pyrin domain; SPRY, SPRY domain.
Figure 2
Figure 2
Inflammation in the gouty joint. Multiple steps in the inflammatory pathway are initiated by MSU deposition in the joint. MSU crystals are recognized by the pattern recognition receptors of the innate immune system, such as the TLRs and are phagocytosed by macrophages. Intracellular MSU crystals are recognized by the NLRP3 inflammasome (a multiprotein complex composed of a C-terminal LRR ‘sensor’ domain, a central nucleotide-binding domain (NACHT domain), which regulates self-oligomerization and an N-terminal PYD) resulting in oligomerization of NLRP3 and cleavage of procaspase-1 to caspase-1. Cathepsin B, ROS, and K+ efflux (stimulated by ATP accumulation) are also understood to have some involvement in the activation and oligomerization of NLRP3 following MSU internalization. Caspase-1 in turn cleaves inactive proIL-1β, transcribed in a NF-κβ-dependent manner following TLR stimulation, to produce active IL-1β, which is released into the extracellular joint fluid. IL-1β activates IL1 receptors on endothelial cells and resident macrophages within the joint, resulting in signal transduction and gene activation and leading to the secretion of an array of proinflammatory cytokines and chemokines. These in turn recruit and activate leukocytes into the joint thereby amplifying the inflammatory cascade. Abbreviations: ASC, apoptosis-associated speck-like protein containing a CARD; CARD, caspase recruitment domain; PYD, Pyrin domain; IL, interleukin; LRR, leucine-rich repeat; MSU, monosodium urate; MyD88, myeloid differentiation primary response gene (88); NACHT, domain present in neuronal apoptosis inhibitor protein (NAIP) major histocompatibility complex class II transactivator; NF-κβ, nuclear factor κβ; NLRP, NACHT domain, LRR domain, and Pyrin domain-containing protein; ROS, reactive oxygen species; TLR, Toll-like receptor.

References

    1. Scheele Carl Wilhelm. Swedish apothecary. JAMA. 1742–1786;1970;212(13):2258–2259.
    1. Freudweiler M. Studies on the nature of gouty tophi. Dtsch Arch Klin Med. 1899;63:266.
    1. Landis RC, Haskard DO. Pathogenesis of crystal-induced inflammation. Curr Rheumatol Rep. 2001;3(1):36–41.
    1. Martin WJ, Walton M, Harper J. Resident macrophages initiating and driving inflammation in a monosodium urate monohydrate crystal-induced murine peritoneal model of acute gout. Arthritis Rheum. 2009;60(1):281–289.
    1. Torres R, Macdonald L, Croll SD, et al. Hyperalgesia, synovitis and multiple biomarkers of inflammation are suppressed by interleukin 1 inhibition in a novel animal model of gouty arthritis. Ann Rheum Dis. 2009;68(10):1602–1608.
    1. Terkeltaub R, Sundy JS, Schumacher HR, et al. The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis: results of a placebo-controlled, monosequence crossover, non-randomised, single-blind pilot study. Ann Rheum Dis. 2009;68(10):1613–1617.
    1. McGonagle D, Tan AL, Shankaranarayana S, Madden J, Emery P, McDermott MF. Management of treatment resistant inflammation of acute on chronic tophaceous gout with anakinra. Ann Rheum Dis. 2007;66(12):1683–1684.
    1. So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther. 2007;9(2):R28.
    1. So A, De Meulemeester M, Pikhlak A, et al. Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: results of a multicenter, phase II, dose-ranging study. Arthritis Rheum. 2010;62(10):3064–3076.
    1. Pelegrin P, Surprenant A. Pannexin-1 couples to maitotoxin- and nigericin-induced interleukin-1beta release through a dye uptake-independent pathway. J Biol Chem. 2007;282(4):2386–2394.
    1. Maitra R, Clement CC, Scharf B, et al. Endosomal damage and TLR2 mediated inflammasome activation by alkane particles in the generation of aseptic osteolysis. Mol Immunol. 2009;47(2–3):175–184.
    1. Hornung V, Bauernfeind F, Halle A, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008;9(8):847–856.
    1. Hacker H, Vabulas RM, Takeuchi O, Hoshino K, Akira S, Wagner H. Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6. J Exp Med. 2000;192(4):595–600.
    1. Mariathasan S, Weiss DS, Newton K, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006;440(7081):228–232.
    1. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440(7081):237–241.
    1. Zhang FX, Kirschning CJ, Mancinelli R, et al. Bacterial lipopolysaccharide activates nuclear factor-kappaB through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes. J Biol Chem. 1999;274(12):7611–7614.
    1. Schwandner R, Dziarski R, Wesche H, Rothe M, Kirschning CJ. Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J Biol Chem. 1999;274(25):17406–17409.
    1. Moors MA, Li L, Mizel SB. Activation of interleukin-1 receptor-associated kinase by gram-negative flagellin. Infect Immun. 2001;69(7):4424–4429.
    1. Frendeus B, Wachtler C, Hedlund M, et al. Escherichia coli P fimbriae utilize the Toll-like receptor 4 pathway for cell activation. Mol Microbiol. 2001;40(1):37–51.
    1. Hedlund M, Frendeus B, Wachtler C, Hang L, Fischer H, Svanborg C. Type 1 fimbriae deliver an LPS- and TLR4-dependent activation signal to CD14-negative cells. Mol Microbiol. 2001;39(3):542–552.
    1. Nociari M, Ocheretina O, Schoggins JW, Falck-Pedersen E. Sensing infection by adenovirus: Toll-like receptor-independent viral DNA recognition signals activation of the interferon regulatory factor 3 master regulator. J Virol. 2007;81(8):4145–4157.
    1. Lin Y, Lee H, Berg AH, Lisanti MP, Shapiro L, Scherer PE. The lipopolysaccharide-activated toll-like receptor (TLR)-4 induces synthesis of the closely related receptor TLR-2 in adipocytes. J Biol Chem. 2000;275(32):24255–24263.
    1. Kawai T, Akira S. Antiviral signaling through pattern recognition receptors. J Biochem. 2007;141(2):137–145.
    1. Martinon F, Agostini L, Meylan E, Tschopp J. Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome. Curr Biol. 2004;14(21):1929–1934.
    1. Craven RR, Gao X, Allen IC, et al. Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells. PLoS One. 2009;4(10):e7446.
    1. Kanneganti TD, Ozoren N, Body-Malapel M, et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature. 2006;440(7081):233–236.
    1. Muruve DA, Petrilli V, Zaiss AK, et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature. 2008;452(7183):103–107.
    1. Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature. 2008;453(7198):1122–1126.
    1. Cassel SL, Eisenbarth SC, Iyer SS, et al. The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci U S A. 2008;105(26):9035–9040.
    1. Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science. 2008;320(5876):674–677.
    1. Inohara N, Chamaillard M, McDonald C, Nunez G. NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Annu Rev Biochem. 2005;74:355–383.
    1. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10(2):417–426.
    1. Martinon F, Tschopp J. Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death Differ. 2007;14(1):10–22.
    1. Petrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 2007;14(9):1583–1589.
    1. Kahlenberg JM, Dubyak GR. Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ release. Am J Physiol Cell Physiol. 2004;286(5):C1100–1108.
    1. Franchi L, Kanneganti TD, Dubyak GR, Nunez G. Differential requirement of P2X7 receptor and intracellular K+ for caspase-1 activation induced by intracellular and extracellular bacteria. J Biol Chem. 2007;282(26):18810–18818.
    1. Halle A, Hornung V, Petzold GC, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 2008;9(8):857–865.
    1. Chu SC, Yang SF, Tzang BS, Hsieh YS, Lue KH, Lu KH. Cathepsin B and cystatin C play an inflammatory role in gouty arthritis of the knee. Clin Chim Acta. 2010;411(21–22):1788–1792.
    1. Meissner F, Molawi K, Zychlinsky A. Superoxide dismutase 1 regulates caspase-1 and endotoxic shock. Nat Immunol. 2008;9(8):866–872.
    1. Netea MG, Nold-Petry CA, Nold MF, et al. Differential requirement for the activation of the inflammasome for processing and release of IL-1beta in monocytes and macrophages. Blood. 2009;113(10):2324–2335.
    1. Roberts TL, Idris A, Dunn JA, et al. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science. 2009;323(5917):1057–1060.
    1. Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009;458(7237):509–513.
    1. Hornung V, Ablasser A, Charrel-Dennis M, et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009;458(7237):514–518.
    1. Burckstummer T, Baumann C, Bluml S, et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat Immunol. 2009;10(3):266–272.
    1. Humke EW, Shriver SK, Starovasnik MA, Fairbrother WJ, Dixit VM. ICEBERG: a novel inhibitor of interleukin-1beta generation. Cell. 2000;103(1):99–111.
    1. Druilhe A, Srinivasula SM, Razmara M, Ahmad M, Alnemri ES. Regulation of IL-1beta generation by Pseudo-ICE and ICEBERG, two dominant negative caspase recruitment domain proteins. Cell Death Differ. 2001;8(6):649–657.
    1. Lamkanfi M, Denecker G, Kalai M, et al. INCA, a novel human caspase recruitment domain protein that inhibits interleukin-1beta generation. J Biol Chem. 2004;279(50):51729–51738.
    1. Scott AM, Saleh M. The inflammatory caspases: guardians against infections and sepsis. Cell Death Differ. 2007;14(1):23–31.
    1. Saleh M, Mathison JC, Wolinski MK, et al. Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice. Nature. 2006;440(7087):1064–1068.
    1. Saleh M, Vaillancourt JP, Graham RK, et al. Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. Nature. 2004;429(6987):75–79.
    1. Guarda G, Dostert C, Staehli F, et al. T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes. Nature. 2009;460(7252):269–273.
    1. Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001;29(3):301–305.
    1. Feldmann J, Prieur AM, Quartier P, et al. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet. 2002;71(1):198–203.
    1. Aganna E, Martinon F, Hawkins PN, et al. Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum. 2002;46(9):2445–2452.
    1. Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity. 2004;20(3):319–325.
    1. Aksentijevich I, Nowak M, Mallah M, et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 2002;46(12):3340–3348.
    1. Brydges SD, Mueller JL, McGeough MD, et al. Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity. Immunity. 2009;30(6):875–887.
    1. Hoffman HM, Firestein GS. Anakinra for the treatment of neonatal-onset multisystem inflammatory disease. Nat Clin Pract Rheumatol. 2006;2(12):646–647.
    1. Goldbach-Mansky R, Dailey NJ, Canna SW, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med. 2006;355(6):581–592.
    1. Hawkins PN, Lachmann HJ, McDermott MF. Interleukin-1-receptor antagonist in the Muckle-Wells syndrome. N Engl J Med. 2003;348(25):2583–2584.
    1. Goldbach-Mansky R, Shroff SD, Wilson M, et al. A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 Trap) in patients with familial cold autoinflammatory syndrome. Arthritis Rheum. 2008;58(8):2432–2442.
    1. Hoffman HM, Throne ML, Amar NJ, et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 2008;58(8):2443–2452.
    1. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med. 2009;360(23):2416–2425.
    1. Lachmann HJ, Lowe P, Felix SD, et al. In vivo regulation of interleukin 1beta in patients with cryopyrin-associated periodic syndromes. J Exp Med. 2009;206(5):1029–1036.
    1. Hoffman HM. Rilonacept for the treatment of cryopyrin-associated periodic syndromes (CAPS) Expert Opin Biol Ther. 2009;9(4):519–531.
    1. Stack JH, Beaumont K, Larsen PD, et al. IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients. J Immunol. 2005;175(4):2630–2634.
    1. Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol. 2009;27:621–668.
    1. Wise CA, Gillum JD, Seidman CE, et al. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet. 2002;11(8):961–969.
    1. Shoham NG, Centola M, Mansfield E, et al. Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci U S A. 2003;100(23):13501–13506.
    1. Verma D, Lerm M, Blomgran Julinder R, Eriksson P, Soderkvist P, Sarndahl E. Gene polymorphisms in the NALP3 inflammasome are associated with interleukin-1 production and severe inflammation: relation to common inflammatory diseases? Arthritis Rheum. 2008;58(3):888–894.
    1. Kastbom A, Verma D, Eriksson P, Skogh T, Wingren G, Soderkvist P. Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project) Rheumatology (Oxford) 2008;47(4):415–417.
    1. Schoultz I, Verma D, Halfvarsson J, et al. Combined polymorphisms in genes encoding the inflammasome components NALP3 and CARD8 confer susceptibility to Crohn’s disease in Swedish men. Am J Gastroenterol. 2009;104(5):1180–1188.
    1. Miao ZM, Zhao SH, Yan SL, et al. NALP3 inflammasome functional polymorphisms and gout susceptibility. Cell Cycle. 2009;8(1):27–30.
    1. Aksentijevich I, Masters SL, Ferguson PJ, et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009;360(23):2426–2437.
    1. Masters SL, Dunne A, Subramanian SL, et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat Immunol. 2010;11(10):897–904.
    1. Duewell P, Kono H, Rayner KJ, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464(7293):1357–1361.
    1. Rajamaki K, Lappalainen J, Oorni K, et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One. 2010;5(7):e11765.
    1. Okamoto M, Liu W, Luo Y, et al. Constitutively active inflammasome in human melanoma cells mediating autoinflammation via caspase-1 processing and secretion of interleukin-1beta. J Biol Chem. 2010;285(9):6477–6488.
    1. Vilaysane A, Chun J, Seamone ME, et al. The NLRP3 inflammasome promotes renal inflammation and contributes to CKD. J Am Soc Nephrol. 2010;21(10):1732–1744.
    1. Kanneganti TD, Body-Malapel M, Amer A, et al. Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J Biol Chem. 2006;281(48):36560–36568.
    1. Allen IC, Scull MA, Moore CB, et al. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity. 2009;30(4):556–565.
    1. Ichinohe T, Lee HK, Ogura Y, Flavell R, Iwasaki A. Inflammasome recognition of influenza virus is essential for adaptive immune responses. J Exp Med. 2009;206(1):79–87.
    1. Kanneganti TD. Central roles of NLRs and inflammasomes in viral infection. Nat Rev Immunol. 2010;10(10):688–698.
    1. Allen IC, TeKippe EM, Woodford RM, et al. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J Exp Med. 2010;207(5):1045–1056.
    1. Yagnik DR, Hillyer P, Marshall D, et al. Noninflammatory phagocytosis of monosodium urate monohydrate crystals by mouse macrophages. Implications for the control of joint inflammation in gout. Arthritis Rheum. 2000;43(8):1779–1789.
    1. Landis RC, Yagnik DR, Florey O, et al. Safe disposal of inflammatory monosodium urate monohydrate crystals by differentiated macrophages. Arthritis Rheum. 2002;46(11):3026–3033.
    1. Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature. 2003;425(6957):516–521.
    1. Joosten LA, Netea MG, Mylona E, et al. Engagement of fatty acids with Toll-like receptor 2 drives interleukin-1beta production via the ASC/caspase 1 pathway in monosodium urate monohydrate crystal-induced gouty arthritis. Arthritis Rheum. 2010;62(11):3237–3248.
    1. Liu-Bryan R, Scott P, Sydlaske A, Rose DM, Terkeltaub R. 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. 2005;52(9):2936–2946.
    1. Chen CJ, Shi Y, Hearn A, et al. MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals. J Clin Invest. 2006;116(8):2262–2271.
    1. Scott P, Ma H, Viriyakosol S, Terkeltaub R, Liu-Bryan R. Engagement of CD14 mediates the inflammatory potential of monosodium urate crystals. J Immunol. 2006;177(9):6370–6378.
    1. Terkeltaub R, Curtiss LK, Tenner AJ, Ginsberg MH. Lipoproteins containing apoprotein B are a major regulator of neutrophil responses to monosodium urate crystals. J Clin Invest. 1984;73(6):1719–1730.
    1. Terkeltaub RA, Dyer CA, Martin J, Curtiss LK. Apolipoprotein (apo) E inhibits the capacity of monosodium urate crystals to stimulate neutrophils. Characterization of intraarticular apo E and demonstration of apo E binding to urate crystals in vivo. J Clin Invest. 1991;87(1):20–26.
    1. Ortiz-Bravo E, Sieck MS, Schumacher HR., Jr Changes in the proteins coating monosodium urate crystals during active and subsiding inflammation. Immunogold studies of synovial fluid from patients with gout and of fluid obtained using the rat subcutaneous air pouch model. Arthritis Rheum. 1993;36(9):1274–1285.
    1. Liote F, Prudhommeaux F, Schiltz C, et al. Inhibition and prevention of monosodium urate monohydrate crystal-induced acute inflammation in vivo by transforming growth factor beta1. Arthritis Rheum. 1996;39(7):1192–1198.
    1. Redini F, Mauviel A, Pronost S, Loyau G, Pujol JP. Transforming growth factor beta exerts opposite effects from interleukin-1 beta on cultured rabbit articular chondrocytes through reduction of interleukin-1 receptor expression. Arthritis Rheum. 1993;36(1):44–50.
    1. Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest. 1998;101(4):890–898.
    1. Bellingan GJ, Caldwell H, Howie SE, Dransfield I, Haslett C. In vivo fate of the inflammatory macrophage during the resolution of inflammation: inflammatory macrophages do not die locally, but emigrate to the draining lymph nodes. J Immunol. 1996;157(6):2577–2585.
    1. Jordan KM, Cameron JS, Snaith M, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford) 2007;46(8):1372–1374.
    1. McGonagle D, Tan AL, Madden J, Emery P, McDermott MF. Successful treatment of resistant pseudogout with anakinra. Arthritis Rheum. 2008;58(2):631–633.
    1. Lasko B, Sheedy B, Hingorani V. RDEA594, a novel uricosuric agent, significantly reduced serum urate levels and was well tolerated in a phase 2a pilot study in hyperuricemic gout patients. Arthritis Rheum. 2009;60:S413–414.

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