Uric acid as a danger signal in gout and its comorbidities (original) (raw)

• Zhu, Y., Pandya, B. J. & Choi, H. K. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007–2008. Arthritis Rheum. 63, 3136–3141 (2011).
  Article PubMed Google Scholar
• Richette, P. & Bardin, T. Gout. Lancet 375, 318–328 (2010).
  Article CAS PubMed Google Scholar
• Pillinger, M. H., Goldfarb, D. S. & Keenan, R. T. Gout and its comorbidities. Bull. NYU Hosp. Jt Dis. 68, 199–203 (2010).
  PubMed Google Scholar
• Shi, Y., Evans, J. E. & Rock, K. L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516–521 (2003).
  Article CAS PubMed Google Scholar
• So, A. & Thorens, B. Uric acid transport and disease. J. Clin. Invest. 120, 1791–1799 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Ames, B. N., Cathcart, R., Schwiers, E. & Hochstein, P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc. Natl Acad. Sci. USA 78, 6858–6862 (1981).
  Article CAS PubMed PubMed Central Google Scholar
• Frayha, R. A., Salti, I. S., Arnaout, A., Khatchadurian, A. & Uthman, S. M. Hereditary xanthinuria: report on three patients and short review of the literature. Nephron 19, 328–332 (1977).
  Article CAS PubMed Google Scholar
• Liu, B. et al. Serum uric acid levels in patients with multiple sclerosis: a meta-analysis. Neurol. Res. 34, 163–171 (2012).
  Article CAS PubMed Google Scholar
• Schwarzschild, M. A. et al. Serum urate as a predictor of clinical and radiographic progression in Parkinson disease. Arch. Neurol. 65, 716–723 (2008).
  Article PubMed PubMed Central Google Scholar
• Alvarez-Lario, B. & Macarron-Vicente, J. Uric acid and evolution. Rheumatology (Oxford) 49, 2010–2015 (2010).
  Article CAS Google Scholar
• Kutzing, M. K. & Firestein, B. L. Altered uric acid levels and disease states. J. Pharmacol. Exp. Ther. 324, 1–7 (2008).
  Article CAS PubMed Google Scholar
• Kumar, H., Kawai, T. & Akira, S. Pathogen recognition by the innate immune system. Int. Rev. Immunol. 30, 16–34 (2011).
  Article CAS PubMed Google Scholar
• Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).
  Article CAS PubMed Google Scholar
• Rock, K. L. & Kono, H. The inflammatory response to cell death. Annu. Rev. Pathol. 3, 99–126 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Banchereau, J. & Steinman, R. M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).
  Article CAS PubMed Google Scholar
• Greenfield, E. A., Nguyen, K. A. & Kuchroo, V. K. CD28/B7 costimulation: a review. Crit. Rev. Immunol. 18, 389–418 (1998).
  Article CAS PubMed Google Scholar
• Rock, K. L., Hearn, A., Chen, C. J. & Shi, Y. Natural endogenous adjuvants. Springer Semin. Immunopathol. 26, 231–246 (2005).
  Article PubMed Google Scholar
• Albert, M. L., Sauter, B. & Bhardwaj, N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392, 86–89 (1998).
  Article CAS PubMed Google Scholar
• Rovere, P. et al. Bystander apoptosis triggers dendritic cell maturation and antigen-presenting function. J. Immunol. 161, 4467–4471 (1998).
  CAS PubMed Google Scholar
• Gallucci, S., Lolkema, M. & Matzinger, P. Natural adjuvants: endogenous activators of dendritic cells. Nat. Med. 5, 1249–1255 (1999).
  Article CAS PubMed Google Scholar
• Shi, Y., Zheng, W. & Rock, K. L. Cell injury releases endogenous adjuvants that stimulate cytotoxic T cell responses. Proc. Natl Acad. Sci. USA 97, 14590–14595 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Kono, H., Chen, C. J., Ontiveros, F. & Rock, K. L. Uric acid promotes an acute inflammatory response to sterile cell death in mice. J. Clin. Invest. 120, 1939–1949 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Kono, H. & Rock, K. L. How dying cells alert the immune system to danger. Nat. Rev. Immunol. 8, 279–289 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Deapen, D. et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum. 35, 311–318 (1992).
  Article CAS PubMed Google Scholar
• Shi, Y., Galusha, S. A. & Rock, K. L. Cutting edge: elimination of an endogenous adjuvant reduces the activation of CD8 T lymphocytes to transplanted cells and in an autoimmune diabetes model. J. Immunol. 176, 3905–3908 (2006).
  Article CAS PubMed Google Scholar
• Allam, R. & Anders, H. J. The role of innate immunity in autoimmune tissue injury. Curr. Opin. Rheumatol. 20, 538–544 (2008).
  Article CAS PubMed Google Scholar
• Like, A. A. & Rossini, A. A. Streptozotocin-induced pancreatic insulitis: new model of diabetes mellitus. Science 193, 415–417 (1976).
  Article CAS PubMed Google Scholar
• Horwitz, M. S., Ilic, A., Fine, C., Rodriguez, E. & Sarvetnick, N. Presented antigen from damaged pancreatic β cells activates autoreactive T cells in virus-mediated autoimmune diabetes. J. Clin. Invest. 109, 79–87 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Kurts, C., Miller, J. F., Subramaniam, R. M., Carbone, F. R. & Heath, W. R. Major histocompatibility complex class I-restricted cross-presentation is biased towards high dose antigens and those released during cellular destruction. J. Exp. Med. 188, 409–414 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Horwitz, M. S. et al. Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry. Nat. Med. 4, 781–785 (1998).
  Article CAS PubMed Google Scholar
• Majno, G. & Joris, I. Cells, tissues, and disease: principles of general pathology 2nd edn (Oxford University Press, New York, 2004).
  Google Scholar
• Kono, H., Karmarkar, D., Iwakura, Y. & Rock, K. L. Identification of the cellular sensor that stimulates the inflammatory response to sterile cell death. J. Immunol. 184, 4470–4478 (2010).
  Article CAS PubMed Google Scholar
• Rock, K. L., Latz, E., Ontiveros, F. & Kono, H. The sterile inflammatory response. Annu. Rev. Immunol. 28, 321–342 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Mertens, M. & Singh, J. A. Anakinra for rheumatoid arthritis: a systematic review. J. Rheumatol. 36, 1118–1125 (2009).
  Article CAS PubMed Google Scholar
• Rock, K. L., Lai, J. J. & Kono, H. Innate and adaptive immune responses to cell death. Immunol. Rev. 243, 191–205 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, C. J. et al. MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals. J. Clin. Invest. 116, 2262–2271 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Gasse, P. et al. Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis. Am. J. Respir. Crit. Care Med. 179, 903–913 (2009).
  Article CAS PubMed Google Scholar
• Dinarello, C. A. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 117, 3720–3732 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Eigenbrod, T., Park, J. H., Harder, J., Iwakura, Y. & Nunez, G. Cutting edge: critical role for mesothelial cells in necrosis-induced inflammation through the recognition of IL-1α released from dying cells. J. Immunol. 181, 8194–8198 (2008).
  Article CAS PubMed Google Scholar
• Gross, O. et al. Inflammasome activators induce interleukin-1α secretion via distinct pathways with differential requirement for the protease function of caspase-1. Immunity 36, 388–400 (2012).
  Article CAS PubMed Google Scholar
• Dinarello, C. A. Immunological and inflammatory functions of the interleukin-1 family. Annu. Rev. Immunol. 27, 519–550 (2009).
  Article CAS PubMed Google Scholar
• Bauernfeind, F. G. et al. Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 183, 787–791 (2009).
  Article CAS PubMed Google Scholar
• Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol. Cell 10, 417–426 (2002).
  Article CAS PubMed Google Scholar
• Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821–832 (2010).
  Article CAS PubMed Google Scholar
• Hoffman, H. M., Mueller, J. L., Broide, D. H., Wanderer, A. A. & Kolodner, R. D. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nat. Genet. 29, 301–305 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Aksentijevich, I. 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. 46, 3340–3348 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Kubota, T. & Koike, R. Cryopyrin-associated periodic syndromes: background and therapeutics. Mod. Rheumatol. 20, 213–221 (2010).
  Article PubMed Google Scholar
• Church, L. D., Churchman, S. M., Hawkins, P. N. & McDermott, M. F. Hereditary auto-inflammatory disorders and biologics. Springer Semin. Immunopathol. 27, 494–508 (2006).
  Article CAS PubMed Google Scholar
• Kobayashi, Y. et al. Identification of calcium-activated neutral protease as a processing enzyme of human interleukin 1α. Proc. Natl Acad. Sci. USA 87, 5548–5552 (1990).
  Article CAS PubMed PubMed Central Google Scholar
• Afonina, I. S. et al. Granzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1α. Mol. Cell 44, 265–278 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Fettelschoss, A. et al. Inflammasome activation and IL-1β target IL-1α for secretion as opposed to surface expression. Proc. Natl Acad. Sci. USA 108, 18055–18060 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Kuida, K. et al. Altered cytokine export and apoptosis in mice deficient in interleukin-1β converting enzyme. Science 267, 2000–2003 (1995).
  Article CAS PubMed Google Scholar
• Sutterwala, F. S. et al. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 24, 317–327 (2006).
  Article CAS PubMed Google Scholar
• Hornung, V. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol. 9, 847–856 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Latz, E. The inflammasomes: mechanisms of activation and function. Curr. Opin. Immunol. 22, 28–33 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Nuki, G. Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. Curr. Rheumatol. Rep. 10, 218–227 (2008).
  Article CAS PubMed Google Scholar
• McCarty, D. J. Urate crystals, inflammation, and colchicine. Arthritis Rheum. 58 (Suppl. S2), S20–S24 (2008).
  Article PubMed Google Scholar
• Eisenbarth, S. C., Colegio, O. R., O'Connor, W., Sutterwala, F. S. & Flavell, R. A. Crucial role for the NALP3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122–1126 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).
  Article CAS PubMed Google Scholar
• Cronstein, B. N. et al. Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils. J. Clin. Invest. 96, 994–1002 (1995).
  Article CAS PubMed PubMed Central Google Scholar
• Dostert, C. et al. Innate immune activation through NALP3 inflammasome sensing of asbestos and silica. Science 320, 674–677 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11, 136–140 (2010).
  Article CAS PubMed Google Scholar
• Bauernfeind, F. et al. Inflammasomes: current understanding and open questions. Cell. Mol. Life Sci. 68, 765–783 (2011).
  Article CAS PubMed Google Scholar
• Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011).
  Article CAS PubMed Google Scholar
• Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat. Immunol. 11, 897–904 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat. Immunol. 9, 857–865 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Hentze, H., Lin, X. Y., Choi, M. S. & Porter, A. G. Critical role for cathepsin B in mediating caspase-1-dependent interleukin-18 maturation and caspase-1-independent necrosis triggered by the microbial toxin nigericin. Cell Death Differ. 10, 956–968 (2003).
  Article CAS PubMed Google Scholar
• Sharp, F. A. et al. Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome. Proc. Natl Acad. Sci. USA 106, 870–875 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Dostert, C. et al. Malarial hemozoin is a NALP3 inflammasome activating danger signal. PLoS ONE 4, e6510 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Gross, O. et al. Syk kinase signalling couples to the NLRP3 inflammasome for anti-fungal host defence. Nature 459, 433–436 (2009).
  Article CAS PubMed Google Scholar
• Hoffstein, S. & Weissmann, G. Mechanisms of lysosomal enzyme release from leukocytes. IV. Interaction of monosodium urate crystals with dogfish and human leukocytes. Arthritis Rheum. 18, 153–165 (1975).
  Article CAS PubMed Google Scholar
• Petrilli, V. et al. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 14, 1583–1589 (2007).
  Article CAS PubMed Google Scholar
• Chen, G. Y. & Nunez, G. Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 10, 826–837 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Leemans, J. C., Cassel, S. L. & Sutterwala, F. S. Sensing damage by the NLRP3 inflammasome. Immunol. Rev. 243, 152–162 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Shimada, K. et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401–414 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Joosten, L. A. et al. Inflammatory arthritis in caspase 1 gene-deficient mice: contribution of proteinase 3 to caspase 1-independent production of bioactive interleukin-1β. Arthritis Rheum. 60, 3651–3662 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Guma, M. et al. Caspase 1-independent activation of interleukin-1β in neutrophil-predominant inflammation. Arthritis Rheum. 60, 3642–3650 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Hazuda, D. J., Strickler, J., Kueppers, F., Simon, P. L. & Young, P. R. Processing of precursor interleukin 1β and inflammatory disease. J. Biol. Chem. 265, 6318–6322 (1990).
  CAS PubMed Google Scholar
• Mizutani, H., Schechter, N., Lazarus, G., Black, R. A. & Kupper, T. S. Rapid and specific conversion of precursor interleukin 1β (IL-1β) to an active IL-1 species by human mast cell chymase. J. Exp. Med. 174, 821–825 (1991).
  Article CAS PubMed Google Scholar
• Schonbeck, U., Mach, F. & Libby, P. Generation of biologically active IL-1β by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1β processing. J. Immunol. 161, 3340–3346 (1998).
  CAS PubMed Google Scholar
• Coeshott, C. et al. Converting enzyme-independent release of tumor necrosis factor α and IL-1β from a stimulated human monocytic cell line in the presence of activated neutrophils or purified proteinase 3. Proc. Natl Acad. Sci. USA 96, 6261–6266 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Pham, C. T. & Ley, T. J. Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo. Proc. Natl Acad. Sci. USA 96, 8627–8632 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• McGuire, M. J., Lipsky, P. E. & Thiele, D. L. Generation of active myeloid and lymphoid granule serine proteases requires processing by the granule thiol protease dipeptidyl peptidase I. J. Biol. Chem. 268, 2458–2467 (1993).
  CAS PubMed Google Scholar
• Adkison, A. M., Raptis, S. Z., Kelley, D. G. & Pham, C. T. Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis. J. Clin. Invest. 109, 363–371 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Liu-Bryan, R., Pritzker, K., Firestein, G. S. & Terkeltaub, R. TLR2 signaling in chondrocytes drives calcium pyrophosphate dihydrate and monosodium urate crystal-induced nitric oxide generation. J. Immunol. 174, 5016–5023 (2005).
  Article CAS PubMed Google Scholar
• Joosten, L. A. et al. 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. Arthritis Rheum. 62, 3237–3248 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Ng, G. et al. Receptor-independent, direct membrane binding leads to cell-surface lipid sorting and Syk kinase activation in dendritic cells. Immunity 29, 807–818 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Scott, P., Ma, H., Viriyakosol, S., Terkeltaub, R. & Liu-Bryan, R. Engagement of CD14 mediates the inflammatory potential of monosodium urate crystals. J. Immunol. 177, 6370–6378 (2006).
  Article CAS PubMed Google Scholar
• Popa-Nita, O., Proulx, S., Pare, G., Rollet-Labelle, E. & Naccache, P. H. Crystal-induced neutrophil activation: XI. Implication and novel roles of classical protein kinase C. J. Immunol. 183, 2104–2114 (2009).
  Article CAS PubMed Google Scholar
• Tramontini, N., Huber, C., Liu-Bryan, R., Terkeltaub, R. A. & Kilgore, K. S. Central role of complement membrane attack complex in monosodium urate crystal-induced neutrophilic rabbit knee synovitis. Arthritis Rheum. 50, 2633–2639 (2004).
  Article PubMed Google Scholar
• Pouliot, M., James, M. J., McColl, S. R., Naccache, P. H. & Cleland, L. G. Monosodium urate microcrystals induce cyclooxygenase-2 in human monocytes. Blood 91, 1769–1776 (1998).
  CAS PubMed Google Scholar
• Kuroda, E. et al. Silica crystals and aluminum salts regulate the production of prostaglandin in macrophages via NALP3 inflammasome-independent mechanisms. Immunity 34, 514–526 (2011).
  Article CAS PubMed Google Scholar
• Krishnan, E. Inflammation, oxidative stress and lipids: the risk triad for atherosclerosis in gout. Rheumatology (Oxford) 49, 1229–1238 (2010).
  Article CAS Google Scholar
• Ichikawa, N., Taniguchi, A., Urano, W., Nakajima, A. & Yamanaka, H. Comorbidities in patients with gout. Nucleosides Nucleotides Nucleic Acids 30, 1045–1050 (2011).
  Article CAS PubMed Google Scholar
• Khosla, U. M. et al. Hyperuricemia induces endothelial dysfunction. Kidney Int. 67, 1739–1742 (2005).
  Article PubMed Google Scholar
• Mazzali, M. et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 38, 1101–1106 (2001).
  Article CAS PubMed Google Scholar
• Mazzali, M. et al. Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am. J. Physiol. Renal Physiol. 282, F991–F997 (2002).
  Article CAS PubMed Google Scholar
• Farquharson, C. A., Butler, R., Hill, A., Belch, J. J. & Struthers, A. D. Allopurinol improves endothelial dysfunction in chronic heart failure. Circulation 106, 221–226 (2002).
  Article CAS PubMed Google Scholar
• Hong, Q. et al. Hyperuricemia induces endothelial dysfunction via mitochondrial Na+/Ca2+ exchanger-mediated mitochondrial calcium overload. Cell Calcium 51, 402–410 (2012).
  Article CAS PubMed Google Scholar
• Puddu, P., Puddu, G. M., Cravero, E., Vizioli, L. & Muscari, A. The relationships among hyperuricemia, endothelial dysfunction, and cardiovascular diseases: molecular mechanisms and clinical implications. J. Cardiol. 59, 235–242 (2012).
  Article PubMed Google Scholar
• Zharikov, S. et al. Uric acid decreases NO production and increases arginase activity in cultured pulmonary artery endothelial cells. Am. J. Physiol. Cell Physiol. 295, C1183–C1190 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Nakagawa, T. et al. A causal role for uric acid in fructose-induced metabolic syndrome. Am. J. Physiol. Renal Physiol. 290, F625–F631 (2006).
  Article CAS PubMed Google Scholar
• Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Dalekos, G. N., Elisaf, M., Bairaktari, E., Tsolas, O. & Siamopoulos, K. C. Increased serum levels of interleukin-1β in the systemic circulation of patients with essential hypertension: additional risk factor for atherogenesis in hypertensive patients? J. Lab. Clin. Med. 129, 300–308 (1997).
  Article CAS PubMed Google Scholar
• Dalekos, G. N., Elisaf, M. S., Papagalanis, N., Tzallas, C. & Siamopoulos, K. C. Elevated interleukin-1β in the circulation of patients with essential hypertension before any drug therapy: a pilot study. Eur. J. Clin. Invest. 26, 936–939 (1996).
  Article CAS PubMed Google Scholar
• Peeters, A. C. et al. Pro-inflammatory cytokines in patients with essential hypertension. Eur. J. Clin. Invest. 31, 31–36 (2001).
  Article CAS PubMed Google Scholar
• Ruggiero, C. et al. Uric acid and inflammatory markers. Eur. Heart J. 27, 1174–1181 (2006).
  Article CAS PubMed Google Scholar
• Vekic, J. et al. High serum uric acid and low-grade inflammation are associated with smaller LDL and HDL particles. Atherosclerosis 203, 236–242 (2009).
  Article CAS PubMed Google Scholar
• Chhana, A. et al. Monosodium urate monohydrate crystals inhibit osteoblast viability and function: implications for development of bone erosion in gout. Ann. Rheum. Dis. 70, 1684–1691 (2011).
  Article CAS PubMed Google Scholar
• Schlesinger, N. & Thiele, R. G. The pathogenesis of bone erosions in gouty arthritis. Ann. Rheum. Dis. 69, 1907–1912 (2010).
  Article CAS PubMed Google Scholar
• So, A., De Smedt, T., Revaz, S. & Tschopp, J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res. Ther. 9, R28 (2007).
  Article PubMed PubMed Central CAS Google Scholar
• Schumacher, H. R. Jr. et al. Rilonacept (interleukin-1 trap) in the prevention of acute gout flares during initiation of urate-lowering therapy: results of a phase II randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 64, 876–884 (2012).
  Article CAS PubMed Google Scholar
• Schlesinger, N. et al. Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study. Ann. Rheum. Dis. 70, 1264–1271 (2011).
  Article CAS PubMed Google Scholar
• Schlesinger, N. et al. Canakinumab relieves symptoms of acute flares and improves health-related quality of life in patients with difficult-to-treat gouty arthritis by suppressing inflammation: results of a randomized, dose-ranging study. Arthritis Res. Ther. 13, R53 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• So, 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. 62, 3064–3076 (2010).
  Article CAS PubMed Google Scholar
• Burnet, F. M. Immunological recognition of self. Science 133, 307–311 (1961).
  Article CAS PubMed Google Scholar
• York, I. A., Goldberg, A. L., Mo, X. Y. & Rock, K. L. Proteolysis and class I major histocompatibility complex antigen presentation. Immunol. Rev. 172, 49–66 (1999).
  Article CAS PubMed Google Scholar
• Germain, R. N. & Margulies, D. H. The biochemistry and cell biology of antigen processing and presentation. Annu. Rev. Immunol. 11, 403–450 (1993).
  Article CAS PubMed Google Scholar
• Hoffman, H. M. et al. Role of the leucine-rich repeat domain of cryopyrin/NALP3 in monosodium urate crystal-induced inflammation in mice. Arthritis Rheum. 62, 2170–2179 (2010).
  CAS PubMed PubMed Central Google Scholar
• Torres, R. 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 68, 1602–1608 (2009).
  Article CAS PubMed Google Scholar
• Cassel, S. L. et al. The NALP3 inflammasome is essential for the development of silicosis. Proc. Natl Acad. Sci. USA 105, 9035–9040 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Palomaki, J. et al. Long, needle-like carbon nanotubes and asbestos activate the NLRP3 inflammasome through a similar mechanism. ACS Nano 5, 6861–6870 (2011).
  Article CAS PubMed Google Scholar
• Rajamaki, K. et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS ONE 5, e11765 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Li, H., Willingham, S. B., Ting, J. P. & Re, F. Cutting edge: inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3. J. Immunol. 181, 17–21 (2008).
  Article CAS PubMed Google Scholar
• Franchi, L. & Nunez, G. The NLRP3 inflammasome is critical for aluminium hydroxide-mediated IL-1β secretion but dispensable for adjuvant activity. Eur. J. Immunol. 38, 2085–2089 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Kool, M. et al. Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J. Immunol. 181, 3755–3759 (2008).
  Article CAS PubMed Google Scholar
• Pazar, B. et al. Basic calcium phosphate crystals induce monocyte/macrophage IL-1β secretion through the NLRP3 inflammasome in vitro. J. Immunol. 186, 2495–2502 (2011).
  Article CAS PubMed Google Scholar
• Narayan, S. et al. Octacalcium phosphate crystals induce inflammation in vivo through interleukin-1 but independent of the NLRP3 inflammasome in mice. Arthritis Rheum. 63, 422–433 (2011).
  Article CAS PubMed Google Scholar
• Jin, C. et al. NLRP3 inflammasome plays a critical role in the pathogenesis of hydroxyapatite-associated arthropathy. Proc. Natl Acad. Sci. USA 108, 14867–14872 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Yazdi, A. S. et al. Nanoparticles activate the NLR pyrin domain containing 3 (NLRP3) inflammasome and cause pulmonary inflammation through release of IL-1α and IL-1β. Proc. Natl Acad. Sci. USA 107, 19449–19454 (2010).
  Article CAS PubMed PubMed Central Google Scholar