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Uric acid as a danger signal in gout and its comorbidities

Abstract

Uric acid is a waste product of purine catabolism. This molecule comes to clinical attention when it nucleates to form crystals of monosodium urate (MSU) in joints or other tissues, and thereby causes the inflammatory disease of gout. Patients with gout frequently suffer from a number of comorbid conditions including hypertension, diabetes mellitus and cardiovascular disease. Why MSU crystals trigger inflammation and are associated with comorbidities of gout has been unclear, but recent studies provide new insights into these issues. Rather than simply being a waste product, uric acid could serve a pathophysiological role as a local alarm signal that alerts the immune system to cell injury and helps to trigger both innate and adaptive immune responses. The inflammatory component of these immune responses is caused when urate crystals trigger both inflammasome-dependent and independent pathways to generate the proinflammatory cytokine IL-1. The resulting bioactive IL-1 stimulates the inflammation of gout and might contribute to the development of other comorbidities. Surprisingly, the same mechanisms underlie the inflammatory response to a number of irritant particles, many of which also cause disease. These new insights help to explain the pathogenesis of gout and point to potential new therapeutic targets for this and other sterile inflammatory diseases.

Key Points

  • The crystallized form of uric acid, monosodium urate (MSU), functions as a danger signal for both adaptive and innate immune responses

  • MSU crystals cause the pathology of gout by activating the inflammatory responses

  • The NLRP3 inflammasome and its downstream effector, IL-1β, are activated by MSU crystals; this pathway is important in sterile inflammation caused by irritant particles (including MSU crystals in gout)

  • Inflammasome-independent mechanisms exist that contribute to particle-induced inflammatory responses

  • Comorbid conditions associated with hyperuricaemia and gout exist that might also be related to uric-acid-induced mediators and inflammation

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Figure 1: Biochemistry of uric acid and its homeostasis.
Figure 2: MHC molecules, antigen presentation and T-cell response.
Figure 3: NLRP3 inflammasome activation.
Figure 4: ROS and cathepsins involved in NLRP3 inflammasome activation.

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Nicola Dalbeth, Hyon K. Choi, … Lisa K. Stamp

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Acknowledgements

This publication was supported by grants from the NIH and American Asthma Foundation to K. L. Rock and by a core support grant from the National Institute of Diabetes and Digestive and Kidney Diseases.

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All authors researched the data for the article and provided a substantial contribution to discussions of the content, and contributed equally to writing the article and to review and/or editing of the manuscript before submission.

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Rock, K., Kataoka, H. & Lai, JJ. Uric acid as a danger signal in gout and its comorbidities. Nat Rev Rheumatol 9, 13–23 (2013). https://doi.org/10.1038/nrrheum.2012.143

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