J Rheum Dis.  2025 Jan;32(1):8-16. 10.4078/jrd.2024.0054.

The pathogenesis of gout

Affiliations
  • 1Division of Rheumatology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea

Abstract

Gout is the most common inflammatory arthritis in adults, associated with hyperuricemia and the chronic deposition of monosodium urate (MSU) crystals. Hyperuricemia results from increased production of uric acid and decreased excretion by the kidneys and intestines. Urate excretion is regulated by a group of urate transporters, and decreased renal or intestinal excretion is the primary mechanism of hyperuricemia in most people. Genetic variability in these urate transporters is strongly related to variances in serum urate levels. Not all individuals with hyperuricemia show deposition of MSU crystals or develop gout. The initiation of the inflammatory response to MSU crystals is mainly mediated by the nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing protein 3 (NLRP3) inflammasome. The activated NLRP3 inflammasome complex cleaves pro-interleukin-1β (IL-1β) into its active form, IL-1β, which is a key mediator of the inflammatory response in gout. IL-1β leads to the upregulation of cytokines and chemokines, resulting in the recruitment of neutrophils and other immune cells. Neutrophils recruited to the site of inflammation also play a role in resolving inflammation. Aggregated neutrophil extracellular traps (NETs) trap and degrade cytokines and chemokines through NET-bound proteases, promoting the resolution of inflammation. Advanced gout is characterized by tophi, chronic inflammatory responses, and structural joint damage. Tophi are chronic foreign body granuloma-like structures containing collections of MSU crystals encased by inflammatory cells and connective tissue. Tophi are closely related to chronic inflammation and structural damage.

Keyword

Gout; Pathogenesis; Uric acid; Inflammasomes

Figure

  • Figure 1 Urate transporters in kidneys and intestines. There are resorptive and secretory urate transporters. In the renal proximal tubule, URAT1, OAT4, OAT10 and GLUT9 act as resorptive urate transporters and ABCG2, NPT4, OAT1 and OAT3 function as secretory urate transporters. ABCG2 is also strongly associated with intestinal urate excretion. URAT1: urate transporter 1, OAT: organic anion transporter, GLUT9: glucose transporter 9, ABCG2: adenosine triphosphate-binding cassette super-family G member 2, NPT4: Na+-phosphate transporter 4.

  • Figure 2 Priming and activation of the NLRP3 inflammasome in gout. Signal 1, the priming process, is mediated by TLRs (TLR2 or TLR4) or cytokine receptors through NF-kB activating pathways. This process controls the gene expression of pro-IL-1β and components of the NLRP3 inflammasome through upregulation of transcriptional level and PTM, preparing cells for inflammasome assembly. In Signal 2, phagocytosis of MSU crystals trigger the assembly of the NLRP3 inflammasome complex and activates caspase-1. Several mechanisms, including ionic K+ efflux, Ca2+ signaling, lysosomal disruption and mitochondrial reactive oxygen generation are known to involve in this process. Activated caspase-1 cleaves pro-IL-1β into IL-1β and also cleaves GSDMD into its amino-terminal fragment (GSDMD N-term) forms pores which facilitates IL-1β release and pyroptosis. TLRs: Toll-like receptors, NF-kB: nuclear factor-κB, IL-1β: interleukin-1β, NLRP3: nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing protein 3, MSU: monosodium urate, PTMs: post-translational modifications, mROS: mitochondrial reactive oxygen species, NEK7: NIMA-related kinase 7, ASC: apoptosis-associated speck-like protein, GSDMD: gasdermin D, NIMA: never in mitosis gene A. Revised from the article of Kingsbury et al. (J Inflamm Res 2011;4:39-49) [37], Bauernfeind et al. (J Immunol 2009;183:787-91) [42], Netea et al. (Blood 2009;113:2324-35) [43], Hornung et al. (Nat Immunol 2008;9:847-56) [51], So and Martinon (Nat Rev Rheumatol 2017;13:639-47) [52], and Kim (J Rheum Dis 2022;29:140-53) [53].


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