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Asymptomatic hyperuricaemia: a silent activator of the innate immune system

Abstract

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.

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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.

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Acknowledgements

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)

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The authors contributed equally to all aspects of the article.

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

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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.

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

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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). https://doi.org/10.1038/s41584-019-0334-3

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