Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Asymptomatic hyperuricaemia: a silent activator of the innate immune system


Asymptomatic hyperuricaemia affects ~20% of the general population in the USA, with variable rates in other countries. Historically, asymptomatic hyperuricaemia was considered a benign laboratory finding with little clinical importance in the absence of gout or kidney stones. Yet, increasing evidence suggests that asymptomatic hyperuricaemia can predict the development of hypertension, obesity, diabetes mellitus and chronic kidney disease and might contribute to disease by stimulating inflammation. Although urate has been classically viewed as an antioxidant with beneficial effects, new data suggest that both crystalline and soluble urate activate various pro-inflammatory pathways. This Review summarizes what is known about the role of urate in the inflammatory response. Further research is needed to define the role of asymptomatic hyperuricaemia in these pro-inflammatory pathways.

Key points

  • Hyperuricaemia is a common laboratory finding that precedes gout and is associated with gout, as well as with hypertension, acute and chronic kidney disease, obesity, metabolic syndrome, fatty liver and diabetes mellitus.

  • The causative role of elevated serum urate in these inflammatory conditions is controversial, but several urate-driven inflammatory mechanisms and other mechanisms have been described.

  • Urate crystals activate the NLRP3 inflammasome and contribute to IL-1β activation through autophagy dysfunction, diminished clearance of damaged organelles, altered redox status and/or AMP-activated protein kinase (AMPK) inhibition.

  • Urate crystals can promote inflammasome-independent mechanisms, such as serine protease-dependent activation of pro-inflammatory cytokines, formation of neutrophil extracellular traps and resolution of inflammation.

  • Soluble urate also has pro-oxidative effects in several cell types and induces inflammatory signalling through several mechanisms, such as MAPK pathway activation, AKT-mTOR activation or AMPK inhibition.

  • Soluble urate and hyperuricaemia exposure could alter the epigenetic programme of innate immune cells and contribute to common adult diseases by promoting persistent inflammatory hyperresponsiveness.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Regulation of serum urate.
Fig. 2: Inflammasome-dependent activation of IL-1β in response to MSU crystals.
Fig. 3: Inflammasome-independent regulation of inflammation in response to MSU crystals.
Fig. 4: Intracellular pro-inflammatory pathways induced by soluble uric acid in vitro.


  1. 1.

    Bursill, D. et al. Gout, hyperuricemia, and crystal-associated disease network consensus statement regarding labels and definitions for disease elements in gout. Arthritis Care Res. 71, 427–434 (2019).

    Google Scholar 

  2. 2.

    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).

    PubMed  Google Scholar 

  3. 3.

    Richette, P. et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann. Rheum. Dis. 76, 29–42 (2017).

    CAS  PubMed  Google Scholar 

  4. 4.

    Sivera, F. et al. Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative. Ann. Rheum. Dis. 73, 328–335 (2014).

    PubMed  Google Scholar 

  5. 5.

    Dalbeth, N. et al. Discordant American College of Physicians and international rheumatology guidelines for gout management: consensus statement of the Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN). Nat. Rev. Rheumatol. 13, 561–568 (2017).

    PubMed  Google Scholar 

  6. 6.

    Khanna, D. et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res. 64, 1431–1446 (2012).

    CAS  Google Scholar 

  7. 7.

    Neogi, T. & Mikuls, T. R. To treat or not to treat (to target) in gout. Ann. Intern. Med. 166, 71–72 (2017).

    PubMed  Google Scholar 

  8. 8.

    Jensen, T. et al. Fructose and sugar: a major mediator of non-alcoholic fatty liver disease. J. Hepatol. 68, 1063–1075 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Johnson, R. J. et al. Hyperuricemia, acute and chronic kidney disease, hypertension, and cardiovascular disease: report of a scientific workshop organized by the national kidney foundation. Am. J. Kidney Dis. 71, 851–865 (2018).

    PubMed  Google Scholar 

  10. 10.

    Grayson, P. C., Kim, S. Y., LaValley, M. & Choi, H. K. Hyperuricemia and incident hypertension: a systematic review and meta-analysis. Arthritis Care Res. 63, 102–110 (2011).

    CAS  Google Scholar 

  11. 11.

    Johnson, R. J. et al. Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes 62, 3307–3315 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Lv, Q. et al. High serum uric acid and increased risk of type 2 diabetes: a systemic review and meta-analysis of prospective cohort studies. PLOS ONE 8, e56864 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Kuwabara, M. et al. Asymptomatic hyperuricemia without comorbidities predicts cardiometabolic diseases: five-year Japanese cohort study. Hypertension 69, 1036–1044 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Yamanaka, H. Japanese Society of Gout and Nucleic Acid Metabolism. Japanese guideline for the management of hyperuricemia and gout: second edition. Nucleosides Nucleotides Nucleic Acids 30, 1018–1029 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Bursill, D., Taylor, W. J., Terkeltaub, R. & Dalbeth, N. The nomenclature of the basic disease elements of gout: a content analysis of contemporary medical journals. Semin. Arthritis Rheum. 48, 456–461 (2018).

    PubMed  Google Scholar 

  16. 16.

    Kahn, K., Serfozo, P. & Tipton, P. A. Identification of the true product of the urate oxidase reaction. J. Am. Chem. Soc. 119, 5435–5442 (1997).

    CAS  Google Scholar 

  17. 17.

    Smith, H. W. From Fish to Philosopher. (Little, Brown and Co, 1953).

  18. 18.

    Poulson, T. L. et al. Uric acid: the main nitrogenous excretory product of birds. Science 170, 98–99 (1970).

    CAS  PubMed  Google Scholar 

  19. 19.

    Kratzer, J. T. et al. Evolutionary history and metabolic insights of ancient mammalian uricases. Proc. Natl Acad. Sci. USA 111, 3763–3768 (2014).

    CAS  PubMed  Google Scholar 

  20. 20.

    Oda, M., Satta, Y., Takenaka, O. & Takahata, N. Loss of urate oxidase activity in hominoids and its evolutionary implications. Mol. Biol. Evol. 19, 640–653 (2002).

    CAS  PubMed  Google Scholar 

  21. 21.

    Johnson, R. J. et al. Theodore E. Woodward Award: the evolution of obesity: insights from the mid-Miocene. Trans. Am. Clin. Climatol. Assoc. 121, 295–308 (2010).

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Tan, P. K., Farrar, J. E., Gaucher, E. A. & Miner, J. N. Coevolution of URAT1 and uricase during primate evolution: implications for serum urate homeostasis and gout. Mol. Biol. Evol. 33, 2193–2200 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Orowan, E. The origin of man. Nature 175, 683–684 (1955).

    CAS  PubMed  Google Scholar 

  24. 24.

    Brooks, G. W. & Mueller, E. Serum urate concentrations among university professors; relation to drive, achievement, and leadership. JAMA 195, 415–418 (1966).

    CAS  PubMed  Google Scholar 

  25. 25.

    Sutin, A. R. et al. Impulsivity is associated with uric acid: evidence from humans and mice. Biol. Psychiatry 75, 31–37 (2014).

    CAS  PubMed  Google Scholar 

  26. 26.

    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).

    CAS  PubMed  Google Scholar 

  27. 27.

    Sevanian, A., Davies, K. J. & Hochstein, P. Serum urate as an antioxidant for ascorbic acid. Am. J. Clin. Nutr. 54, 1129S–1134S (1991).

    CAS  PubMed  Google Scholar 

  28. 28.

    Watanabe, S. et al. Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity. Hypertension 40, 355–360 (2002).

    CAS  PubMed  Google Scholar 

  29. 29.

    Johnson, R. J. & Andrews, P. Fructose, uricase, and the back-to-Africa hypothesis. Evol. Anthropol. 19, 250–257 (2010).

    Google Scholar 

  30. 30.

    Cicerchi, C. et al. Uric acid-dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids. FASEB J. 28, 3339–3350 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Gersch, C. et al. Inactivation of nitric oxide by uric acid. Nucleosides Nucleotides Nucleic Acids 27, 967–978 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Imaram, W. et al. Radicals in the reaction between peroxynitrite and uric acid identified by electron spin resonance spectroscopy and liquid chromatography mass spectrometry. Free Radic. Biol. Med. 49, 275–281 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Johnson, R. J., Titte, S., Cade, J. R., Rideout, B. A. & Oliver, W. J. Uric acid, evolution and primitive cultures. Semin. Nephrol. 25, 3–8 (2005).

    CAS  PubMed  Google Scholar 

  34. 34.

    Kottgen, A. et al. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat. Genet. 45, 145–154 (2013).

    PubMed  Google Scholar 

  35. 35.

    Nakatochi, M. et al. Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals. Commun. Biol. 2, 115 (2019).

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Major, T. J., Dalbeth, N., Stahl, E. A. & Merriman, T. R. An update on the genetics of hyperuricaemia and gout. Nat. Rev. Rheumatol. 14, 341–353 (2018).

    CAS  PubMed  Google Scholar 

  37. 37.

    Tin, A. et al. Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels. Nat. Commun. 9, 4228 (2018).

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Johnson, R. J. et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 41, 1183–1190 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Neogi, T. Gout. Ann. Intern. Med. 165, ITC1–ITC16 (2016).

    PubMed  Google Scholar 

  40. 40.

    Choi, H. K., Atkinson, K., Karlson, E. W., Willett, W. & Curhan, G. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N. Engl. J. Med. 350, 1093–1103 (2004).

    CAS  PubMed  Google Scholar 

  41. 41.

    Quinones, G. A. et al. Effect of insulin on uric acid excretion in humans. Am. J. Physiol. 268, E1–E5 (1995).

    Google Scholar 

  42. 42.

    Kahn, A. M. Effect of diuretics on the renal handling of urate. Semin. Nephrol. 8, 305–314 (1988).

    CAS  PubMed  Google Scholar 

  43. 43.

    Lee, S. M. et al. Low serum uric acid level is a risk factor for death in incident hemodialysis patients. Am. J. Nephrol. 29, 79–85 (2009).

    CAS  PubMed  Google Scholar 

  44. 44.

    Suliman, M. E. et al. J-shaped mortality relationship for uric acid in CKD. Am. J. Kidney Dis. 48, 761–771 (2006).

    CAS  PubMed  Google Scholar 

  45. 45.

    Kuo, C. F., Grainge, M. J., Zhang, W. & Doherty, M. Global epidemiology of gout: prevalence, incidence and risk factors. Nat. Rev. Rheumatol. 11, 649–662 (2015).

    PubMed  Google Scholar 

  46. 46.

    Faires, J. S. & McCarty, D. J. Acute arthritis in man and dog after intrasynovial injection of sodium urate crystals. Lancet 280, 682–685 (1962).

    Google Scholar 

  47. 47.

    Shimizu, T., Hori, H., Umeyama, M. & Shimizu, K. Characteristics of gout patients according to the laterality of nephrolithiasis: a cross-sectional study using helical computed tomography. Int. J. Rheum. Dis. 22, 567–573 (2019).

    CAS  PubMed  Google Scholar 

  48. 48.

    Landgren, A. J. et al. Incidence of and risk factors for nephrolithiasis in patients with gout and the general population, a cohort study. Arthritis Res. Ther. 19, 173 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Marchini, G. S., Sarkissian, C., Tian, D., Gebreselassie, S. & Monga, M. Gout, stone composition and urinary stone risk: a matched case comparative study. J. Urol. 189, 1334–1339 (2013).

    PubMed  Google Scholar 

  50. 50.

    Hahn, K., Kanbay, M., Lanaspa, M. A., Johnson, R. J. & Ejaz, A. A. Serum uric acid and acute kidney injury: a mini review. J. Adv. Res. 8, 529–536 (2017).

    CAS  PubMed  Google Scholar 

  51. 51.

    Shimada, M. et al. A novel role for uric acid in acute kidney injury associated with tumour lysis syndrome. Nephrol. Dial. Transpl. 24, 2960–2964 (2009).

    CAS  Google Scholar 

  52. 52.

    Roncal-Jimenez, C. et al. Heat stress nephropathy from exercise-induced uric acid crystalluria: a perspective on Mesoamerican nephropathy. Am. J. Kidney Dis. 67, 20–30 (2016).

    CAS  PubMed  Google Scholar 

  53. 53.

    Ryu, E. S. et al. Uric acid-induced phenotypic transition of renal tubular cells as a novel mechanism of chronic kidney disease. Am. J. Physiol. Ren. Physiol. 304, F471–F480 (2013).

    CAS  Google Scholar 

  54. 54.

    Zhou, Y. et al. Uric acid induces renal inflammation via activating tubular NF-κB signaling pathway. PLOS ONE 7, e39738 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Verzola, D. et al. Uric acid promotes apoptosis in human proximal tubule cells by oxidative stress and the activation of NADPH oxidase NOX 4. PLOS ONE 9, e115210 (2014).

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    Keenan, T. et al. Causal assessment of serum urate levels in cardiometabolic diseases through a mendelian randomization study. J. Am. Coll. Cardiol. 67, 407–416 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    White, J. et al. Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis. Lancet Diabetes Endocrinol. 4, 327–336 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Jordan, D. M. et al. No causal effects of serum urate levels on the risk of chronic kidney disease: a Mendelian randomization study. PLOS Med. 16, e1002725 (2019).

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Johnson, R. J., Merriman, T. & Lanaspa, M. A. Causal or noncausal relationship of uric acid with diabetes. Diabetes 64, 2720–2722 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Su, X., Xu, B., Yan, B., Qiao, X. & Wang, L. Effects of uric acid-lowering therapy in patients with chronic kidney disease: a meta-analysis. PLOS ONE 12, e0187550 (2017).

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Qu, L. H., Jiang, H. & Chen, J. H. Effect of uric acid-lowering therapy on blood pressure: systematic review and meta-analysis. Ann. Med. 49, 142–156 (2017).

    CAS  PubMed  Google Scholar 

  62. 62.

    Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

    CAS  PubMed  Google Scholar 

  63. 63.

    Dinarello, C. A. A clinical perspective of IL-1β as the gatekeeper of inflammation. Eur. J. Immunol. 41, 1203–1217 (2011).

    CAS  PubMed  Google Scholar 

  64. 64.

    Dinarello, C. A. The history of fever, leukocytic pyrogen and interleukin-1. Temperature 2, 8–16 (2015).

    Google Scholar 

  65. 65.

    Gross, O., Thomas, C. J., Guarda, G. & Tschopp, J. The inflammasome: an integrated view. Immunol. Rev. 243, 136–151 (2011).

    CAS  PubMed  Google Scholar 

  66. 66.

    Kelley, N., Jeltema, D., Duan, Y. & He, Y. The NLRP3 inflammasome: an overview of mechanisms of activation and regulation. Int. J. Mol. Sci. 20, E3328 (2019).

    PubMed  Google Scholar 

  67. 67.

    Netea, M. G. et al. Differential requirement for the activation of the inflammasome for processing and release of IL-1β in monocytes and macrophages. Blood 113, 2324–2335 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Misawa, T. et al. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat. Immunol. 14, 454–460 (2013).

    CAS  PubMed  Google Scholar 

  69. 69.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Jhang, J. J., Cheng, Y. T., Ho, C. Y. & Yen, G. C. Monosodium urate crystals trigger Nrf2- and heme oxygenase-1-dependent inflammation in THP-1 cells. Cell Mol. Immunol. 12, 424–434 (2015).

    CAS  PubMed  Google Scholar 

  71. 71.

    Kim, S. K., Choe, J. Y. & Park, K. Y. Enhanced p62 is responsible for mitochondrial pathway-dependent apoptosis and interleukin-1β production at the early phase by monosodium urate crystals in murine macrophage. Inflammation 39, 1603–1616 (2016).

    CAS  PubMed  Google Scholar 

  72. 72.

    Wang, Y., Viollet, B., Terkeltaub, R. & Liu-Bryan, R. AMP-activated protein kinase suppresses urate crystal-induced inflammation and transduces colchicine effects in macrophages. Ann. Rheum. Dis. 75, 286–294 (2014).

    PubMed  PubMed Central  Google Scholar 

  73. 73.

    Vazirpanah, N. et al. mTOR inhibition by metformin impacts monosodium urate crystal-induced inflammation and cell death in gout: a prelude to a new add-on therapy? Ann. Rheumat. Dis. 78, 663–671 (2019).

    CAS  PubMed  Google Scholar 

  74. 74.

    Cumpelik, A., Ankli, B., Zecher, D. & Schifferli, J. A. Neutrophil microvesicles resolve gout by inhibiting C5a-mediated priming of the inflammasome. Ann. Rheum. Dis. 75, 1236–1245 (2016).

    CAS  PubMed  Google Scholar 

  75. 75.

    Russell, I. J., Mansen, C., Kolb, L. M. & Kolb, W. P. Activation of the fifth component of human complement (C5) induced by monosodium urate crystals: C5 convertase assembly on the crystal surface. Clin. Immunol. Immunopathol. 24, 239–250 (1982).

    CAS  PubMed  Google Scholar 

  76. 76.

    Netea, M. G., van de Veerdonk, F. L., van der Meer, J. W., Dinarello, C. A. & Joosten, L. A. Inflammasome-independent regulation of IL-1-family cytokines. Ann. Rev. Immunol. 33, 49–77 (2015).

    CAS  Google Scholar 

  77. 77.

    Cho, J. S. et al. Neutrophil-derived IL-1β is sufficient for abscess formation in immunity against Staphylococcus aureus in mice. PLOS Pathog. 8, e1003047 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Schreiber, A. et al. Neutrophil serine proteases promote IL-1β generation and injury in necrotizing crescentic glomerulonephritis. J. Am. Soc. Nephrol. 23, 470–482 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Joosten, L. A. et al. Alpha-1-anti-trypsin-Fc fusion protein ameliorates gouty arthritis by reducing release and extracellular processing of IL-1β and by the induction of endogenous IL-1Ra. Ann. Rheumat. Dis. 75, 1219–1227 (2015).

    PubMed  Google Scholar 

  80. 80.

    Hahn, J. et al. Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of cytokines and chemokines and protection from antiproteases. FASEB J. 33, 1401–1414 (2018).

    PubMed  PubMed Central  Google Scholar 

  81. 81.

    Schauer, C. et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat. Med. 20, 511–517 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Schorn, C. et al. Bonding the foe-NETting neutrophils immobilize the pro-inflammatory monosodium urate crystals. Front. Immunol. 3, 376 (2012).

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Reber, L. L., Gaudenzio, N., Starkl, P. & Galli, S. J. Neutrophils are not required for resolution of acute gouty arthritis in mice. Nat. Med. 22, 1382–1384 (2016).

    CAS  PubMed  Google Scholar 

  84. 84.

    Reinwald, C. et al. Reply to “Neutrophils are not required for resolution of acute gouty arthritis in mice”. Nat. Med. 22, 1384–1386 (2016).

    CAS  PubMed  Google Scholar 

  85. 85.

    Desai, J., Steiger, S. & Anders, H. J. Molecular pathophysiology of gout. Trends Mol. Med. 23, 756–768 (2017).

    CAS  PubMed  Google Scholar 

  86. 86.

    Manfredi, A. A., Ramirez, G. A., Rovere-Querini, P. & Maugeri, N. The neutrophil’s choice: phagocytose vs make neutrophil extracellular traps. Front. Immunol. 9, 288 (2018).

    PubMed  PubMed Central  Google Scholar 

  87. 87.

    Gersch, C. et al. Reactions of peroxynitrite with uric acid: formation of reactive intermediates, alkylated products and triuret, and in vivo production of triuret under conditions of oxidative stress. Nucleosides Nucleotides Nucleic Acids 28, 118–149 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Meotti, F. C. et al. Urate as a physiological substrate for myeloperoxidase: implications for hyperuricemia and inflammation. J. Biol. Chem. 286, 12901–12911 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Corry, D. B. et al. Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system. J. Hypertens. 26, 269–275 (2008).

    CAS  PubMed  Google Scholar 

  90. 90.

    Yu, M. A., Sanchez-Lozada, L. G., Johnson, R. J. & Kang, D. H. Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction. J. Hypertens. 28, 1234–1242 (2010).

    PubMed  Google Scholar 

  91. 91.

    Sautin, Y. Y., Nakagawa, T., Zharikov, S. & Johnson, R. J. Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am. J. Physiol. Cell Physiol. 293, C584–C596 (2007).

    CAS  PubMed  Google Scholar 

  92. 92.

    Lanaspa, M. A. et al. Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver. J. Biol. Chem. 287, 40732–40744 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Roncal-Jimenez, C. A. et al. Sucrose induces fatty liver and pancreatic inflammation in male breeder rats independent of excess energy intake. Metabolism 60, 1259–1270 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Cirillo, P. et al. Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells. J. Am. Soc. Nephrol. 20, 545–553 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Choi, Y. J. et al. Uric acid induces endothelial dysfunction by vascular insulin resistance associated with the impairment of nitric oxide synthesis. FASEB J. 28, 3197–3204 (2014).

    CAS  PubMed  Google Scholar 

  96. 96.

    Sanchez-Lozada, L. G. et al. Uric acid-induced endothelial dysfunction is associated with mitochondrial alterations and decreased intracellular ATP concentrations. Nephron Exp. Nephrol. 121, e71–e78 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Martinon, F. Signaling by ROS drives inflammasome activation. Eur. J. Immunol. 40, 616–619 (2010).

    CAS  PubMed  Google Scholar 

  98. 98.

    Crisan, T. O. et al. Uric acid priming in human monocytes is driven by the AKT-PRAS40 autophagy pathway. Proc. Natl Acad. Sci. USA 114, 5485–5490 (2017).

    CAS  PubMed  Google Scholar 

  99. 99.

    Alberts, B. M. et al. Secretion of IL-1β from monocytes in gout is redoxindependent. Front. Immunol. 10, 70 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Kang, D. H., Park, S. K., Lee, I. K. & Johnson, R. J. Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J. Am. Soc. Nephrol. 16, 3553–3562 (2005).

    CAS  PubMed  Google Scholar 

  101. 101.

    Kanellis, J. et al. Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension 41, 1287–1293 (2003).

    CAS  PubMed  Google Scholar 

  102. 102.

    Xu, C. et al. Activation of renal (Pro)renin receptor contributes to high fructose-induced salt sensitivity. Hypertension 69, 339–348 (2017).

    CAS  PubMed  Google Scholar 

  103. 103.

    Kang, D. H. et al. A role for uric acid in the progression of renal disease. J. Am. Soc. Nephrol. 13, 2888–2897 (2002).

    CAS  PubMed  Google Scholar 

  104. 104.

    Rao, G. N., Corson, M. A. & Berk, B. C. Uric acid stimulates vascular smooth muscle cell proliferation by increasing platelet-derived growth factor A-chain expression. J. Biol. Chem. 266, 8604–8608 (1991).

    CAS  PubMed  Google Scholar 

  105. 105.

    Braga, T. T. et al. Soluble uric acid activates the NLRP3 inflammasome. Sci. Rep. 7, 39884 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Netea, M. G., Kullberg, B. J., Blok, W. L., Netea, R. T. & van der Meer, J. W. The role of hyperuricemia in the increased cytokine production after lipopolysaccharide challenge in neutropenic mice. Blood 89, 577–582 (1997).

    CAS  PubMed  Google Scholar 

  107. 107.

    Jia, L. et al. Hyperuricemia causes pancreatic β-cell death and dysfunction through NF-κB signaling pathway. PLOS ONE 8, e78284 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Lu, W. et al. Uric acid produces an inflammatory response through activation of NF-κB in the hypothalamus: implications for the pathogenesis of metabolic disorders. Sci. Rep. 5, 12144 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Crisan, T. O. et al. Soluble uric acid primes TLR-induced proinflammatory cytokine production by human primary cells via inhibition of IL-1Ra. Ann. Rheum. Dis. 75, 755–762 (2015).

    PubMed  Google Scholar 

  110. 110.

    Cheng, Z. The FoxO-autophagy axis in health and disease. Trends Endocrinol. Metab. 30, 658–671 (2019).

    CAS  PubMed  Google Scholar 

  111. 111.

    Wiza, C., Nascimento, E. B. & Ouwens, D. M. Role of PRAS40 in Akt and mTOR signaling in health and disease. Am. J. Physiol. Endocrinol. Metab. 302, E1453–E1460 (2012).

    CAS  PubMed  Google Scholar 

  112. 112.

    Dunlop, E. A. & Tee, A. R. mTOR and autophagy: a dynamic relationship governed by nutrients and energy. Semin. Cell Dev. Biol. 36, 121–129 (2014).

    CAS  PubMed  Google Scholar 

  113. 113.

    Saitoh, T. et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production. Nature 456, 264–268 (2008).

    CAS  PubMed  Google Scholar 

  114. 114.

    Crisan, T. O. et al. Inflammasome-independent modulation of cytokine response by autophagy in human cells. PLOS ONE 6, e18666 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Harris, J. et al. Autophagy controls IL-1β secretion by targeting pro-IL-1β for degradation. J. Biol. Chem. 286, 9587–9597 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Buffen, K. et al. Autophagy suppresses host adaptive immune responses toward Borrelia burgdorferi. J. Leukoc. Biol. 100, 589–598 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Garcia, D. & Shaw, R. J. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol. Cell 66, 789–800 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    O’Neill, L. A. & Hardie, D. G. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493, 346–355 (2013).

    PubMed  Google Scholar 

  119. 119.

    Lanaspa, M. A. et al. Counteracting roles of AMP deaminase and AMP kinase in the development of fatty liver. PLOS ONE 7, e48801 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Luo, C. et al. High uric acid activates the ROS-AMPK pathway, impairs CD68 expression and inhibits OxLDL-induced foam-cell formation in a human monocytic cell line, THP-1. Cell Physiol. Biochem. 40, 538–548 (2016).

    CAS  PubMed  Google Scholar 

  121. 121.

    Yuan, H. et al. Metformin ameliorates high uric acid-induced insulin resistance in skeletal muscle cells. Mol. Cell Endocrinol. 443, 138–145 (2017).

    CAS  PubMed  Google Scholar 

  122. 122.

    Netea, M. G., Quintin, J. & van der Meer, J. W. Trained immunity: a memory for innate host defense. Cell Host Microbe 9, 355–361 (2011).

    CAS  PubMed  Google Scholar 

  123. 123.

    Saeed, S. et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345, 1251086 (2014).

    PubMed  PubMed Central  Google Scholar 

  124. 124.

    Novakovic, B. et al. β-glucan reverses the epigenetic state of LPS-induced immunological tolerance. Cell 167, 1354–1368.e14 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Blok, B. A., Arts, R. J., van Crevel, R., Benn, C. S. & Netea, M. G. Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines. J. Leukoc. Biol. 98, 347–356 (2015).

    CAS  PubMed  Google Scholar 

  126. 126.

    Crisan, T. O., Netea, M. G. & Joosten, L. A. Innate immune memory: implications for host responses to damage-associated molecular patterns. Eur. J. Immunol. 46, 817–828 (2016).

    CAS  PubMed  Google Scholar 

  127. 127.

    Rajasekar, P., O’Neill, C. L., Eeles, L., Stitt, A. W. & Medina, R. J. Epigenetic changes in endothelial progenitors as a possible cellular basis for glycemic memory in diabetic vascular complications. J. Diabetes Res. 2015, 436879 (2015).

    PubMed  PubMed Central  Google Scholar 

  128. 128.

    Bekkering, S. et al. Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes. Arterioscler. Thromb. Vasc. Biol. 34, 1731–1738 (2014).

    CAS  PubMed  Google Scholar 

  129. 129.

    Bekkering, S. et al. Treatment with statins does not revert trained immunity in patients with familial hypercholesterolemia. Cell Metab. 30, 1–2 (2019).

    CAS  PubMed  Google Scholar 

  130. 130.

    Ruggiero, C. et al. Uric acid and inflammatory markers. Eur. Heart J. 27, 1174–1181 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Grainger, R., McLaughlin, R. J., Harrison, A. A. & Harper, J. L. Hyperuricaemia elevates circulating CCL2 levels and primes monocyte trafficking in subjects with inter-critical gout. Rheumatology 52, 1018–1021 (2013).

    CAS  PubMed  Google Scholar 

  132. 132.

    Gao, L. et al. Male asymptomatic hyperuricemia patients display a lower number of NKG2D+ NK cells before and after a low-purine diet. Medicine 97, e13668 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Mylona, E. E. et al. Enhanced interleukin-1β production of PBMCs from patients with gout after stimulation with Toll-like receptor-2 ligands and urate crystals. Arthritis Res. Ther. 14, R158 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Tanaka, T. et al. A double blind placebo controlled randomized trial of the effect of acute uric acid changes on inflammatory markers in humans: a pilot study. PLOS ONE 12, e0181100 (2017).

    PubMed  PubMed Central  Google Scholar 

  135. 135.

    Abhishek, A., Valdes, A. M., Zhang, W. & Doherty, M. Association of serum uric acid and disease duration with frequent gout attacks: a case-control study. Arthritis Care Res. 68, 1573–1577 (2016).

    CAS  Google Scholar 

  136. 136.

    Griffith, J. W., Sun, T., McIntosh, M. T. & Bucala, R. Pure hemozoin is inflammatory in vivo and activates the NALP3 inflammasome via release of uric acid. J. Immunol. 183, 5208–5220 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Orengo, J. M. et al. Uric acid is a mediator of the Plasmodium falciparum-induced inflammatory response. PLOS ONE 4, e5194 (2009).

    PubMed  PubMed Central  Google Scholar 

  138. 138.

    Shriner, D. et al. Evolutionary context for the association of γ-globin, serum uric acid, and hypertension in African Americans. BMC Med. Genet. 16, 103 (2015).

    PubMed  PubMed Central  Google Scholar 

  139. 139.

    Spaetgens, B. et al. Risk of infections in patients with gout: a population-based cohort study. Sci. Rep. 7, 1429 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Bardin, T. & Richette, P. Definition of hyperuricemia and gouty conditions. Curr. Opin. Rheumatol. 26, 186–191 (2014).

    CAS  PubMed  Google Scholar 

  141. 141.

    Inaba, S., Sautin, Y., Garcia, G. E. & Johnson, R. J. What can asymptomatic hyperuricaemia and systemic inflammation in the absence of gout tell us? Rheumatology 52, 963–965 (2013).

    PubMed  Google Scholar 

  142. 142.

    Dalbeth, N. et al. Urate crystal deposition in asymptomatic hyperuricaemia and symptomatic gout: a dual energy CT study. Ann. Rheumat. Dis. 74, 908–911 (2015).

    PubMed  Google Scholar 

  143. 143.

    Perez-Ruiz, F., Marimon, E. & Chinchilla, S. P. Hyperuricaemia with deposition: latest evidence and therapeutic approach. Ther. Adv. Musculoskelet. Dis. 7, 225–233 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Asghar, Z. A. et al. Maternal fructose drives placental uric acid production leading to adverse fetal outcomes. Sci. Rep. 6, 25091 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Sato, Y. et al. The case for uric acid- lowering treatment in patients with hyperuricaemia and CKD. Nat. Rev. Nephrol. 15, 767–775 (2019).

    Google Scholar 

Download references


The work by L.A.B.J. and T.O.C. is supported by a Competitiveness Operational Programme grant of the Romanian Ministry of European Funds (P_37_762, MySMIS 103587). The work of P.B. is supported by the National Institute of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the Diabetic Complications Consortium (DiaComp), the Juvenile Diabetes Research Foundation (JDRF), the Thrasher Research Fund, Center for Women’s Health Research and the International Society for Paediatric and Adolescent Diabetes (ISPAD). The work by R.J.J. is supported by grants from the NIH (NIDDK 1RO1DK109408-01A1 and NIDDK R01 DK108859-01)

Author information




The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Leo A. B. Joosten or Richard J. Johnson.

Ethics declarations

Competing interests

R.J.J. declares that he is an inventor on several patents and patent applications related to the role of fructose and urate metabolism in hypertension, metabolic syndrome and kidney disease. He also has equity with XORTX therapeutics, which is developing novel xanthine oxidase inhibitors, and Colorado Research Partners LLC, which is developing inhibitors of fructose metabolism. Finally, he has received honoraria from Astra Zeneca, Eli Lilly and Horizon Pharmaceuticals. P.B. declares that he has received consulting fees or speaking honoraria or both from Horizon Pharma, Boehringer Ingelheim, Bayer, and Bristol-Myers Squibb. He also serves on a scientific advisory board for XORTX Therapeutics. L.A.B.J. and T.O.C. declare that they have no competing interests.

Additional information

Peer review information

Nature Reviews Rheumatology thanks P. Richette and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Joosten, L.A.B., Crişan, T.O., Bjornstad, P. et al. Asymptomatic hyperuricaemia: a silent activator of the innate immune system. Nat Rev Rheumatol 16, 75–86 (2020).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing