The pathogenesis of gout

Eun Young Ahn; Min Wook So

doi:10.4078/jrd.2024.0054

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Ahn and So: The pathogenesis of gout

Review Article

J Rheum Dis 2025;32(1):8-16.

Published online: 6 November 2024

DOI: https://doi.org/10.4078/jrd.2024.0054

The pathogenesis of gout

Eun Young Ahn, M.D.

, Min Wook So, M.D., Ph.D.

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

Corresponding author: Min Wook So, https://orcid.org/0000-0001-5027-0410 Division of Rheumatology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan 50612, Korea. E-mail: 99soting@pusan.ac.kr

Received 2 May 2024 Revised 19 September 2024 Accepted 24 October 2024

(open-access):

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.

Keywords: Gout, Pathogenesis, Uric acid, Inflammasomes

INTRODUCTION

Gout is the most common inflammatory arthritis in adults, associated with hyperuricemia and chronic deposition of monosodium urate (MSU) crystals. The prevalence of gout and its incidence is increasing all around the world [1]. The typical presentation of gout is an acute onset of severe pain and swelling, usually in a joint of the lower limb, which can also involve periarticular tissues (bursa, tendons), resolving within 7~14 days. After resolution, there is a pain-free asymptomatic period until another gout flare occurs [2].

The development of gout involves several stages. Hyperuricemia is a prerequisite factor for the development of gout, but not all individuals with hyperuricemia develop gout. MSU crystal deposition occurs in some individuals with hyperuricemia. In response to the deposited crystals, an acute inflammatory response can occur, known as a gout flare. A typical characteristic of gout flares is self-resolution. With a long duration of gout, tophi occurs, which can result in chronic granulomatous inflammatory responses and structural joint damage.

MAIN SUBJECTS

Hyperuricemia

Hyperuricemia is essential for the development of gout but not all individuals with hyperuricemia develop gout. About 22% of males who had serum urate level greater than 9.0 mg/dL develop gout in 5 years [3]. Urate is the salt of uric acid, product of purine metabolism. Purines, derived from dietary sources and cellular turnover, are broken down into uric acid through a series of enzymatic reactions, primarily involving xanthine oxidase. Most uric acid circulates as the urate anion and uric acid is only marginally soluble.

Uric acid can be metabolized into allantoin by uricase in most mammals, and allantoin is highly water-soluble and readily excreted. However, humans and certain other primates, including chimpanzees, gorillas, orangutans and gibbons, lack uricase, so uric acid is the end product of purine metabolism [4].

Hyperuricemia is associated with increased production of uric acid and decreased excretion by the kidneys and intestine. Increased consumption of purine-rich foods such as meat or seafood, rather than high-purine foods of plant origin, is associated with an increased risk of gout [5,6]. Alcohol and high fructose intake are also associated with the risk of gout [7,8]. However, diet appears to have a smaller effect on serum uric acid levels than genetic variants on serum urate levels or the risk of gout [9 -11]. There might be additive gene-diet interactions. In a recent cohort study in the UK, the impact of diet on gout risk was larger in females with a higher genetic score [12]. This suggests that dietary factors can amplify the effects of genetic predisposition on risk of gout.

Underexcretion of urate, either through decreased renal or intestinal excretion, is the main mechanism of hyperuricemia in most people. Urate excretion is regulated by a group of urate transporters in proximal tubules of kidney and intestine. Approximately two-thirds of urate excretion occurs in the kidneys, while the remaining one-third occurs in the intestine [13]. In the kidney, urate is freely filtered by renal glomeruli and approximately 90 percent of filtered urate is reabsorbed in the proximal tubule by a group of urate transporters.

There are resorptive and secretary urate transporters on apical and basolateral membrane of renal proximal tubule cells (Figure 1). Urate transporter 1 (URAT1) is a major apical resorptive urate transporter and it is a member of the organic anion transporter (OAT) family. URAT1 has the highest affinity for urate exchange with aromatic organic anions, such as nicotinate and pyrazinoate, followed by lactate, beta-hydroxybutyrate, and acetoacetate. Uricosuric drugs such as probenecid, benzbromarone, fenofibrate, and losartan are potent inhibitors of URAT1 [14]. OAT4 and OAT10 are two other known urate resorptive transporters, which are located on apical membrane of renal proximal tubule cells. Glucose transporter 9 (GLUT9) is a major urate resorptive transporter located on basolateral membrane of the proximal tubule, which transports urate back into the blood [13].

In addition to transporters that reabsorb urate, there is another set of transporters that mediate urate secretion in the proximal tubule. Adenosine triphosphate (ATP)-binding cassette super-family G member 2 (ABCG2), Na⁺-phosphate transporter 1 (NPT1), and NPT4 transporter is on the apical membrane. OAT1 and OAT3 are located on the basolateral membrane, transporting urate in exchange with α-ketoglutarate. Especially, ABCG2 plays a crucial role not only in renal but also in the intestinal urate excretions. ABCG2 is strongly associated with intestinal urate excretion, and dysfunction in ABCG2 results in extrarenal urate underexcretion and renal overload hyperuricemia [14,15].

Genetic variability in these urate transporters is strongly related to variances in serum urate levels. The urate transporter genes SLC2A9 (encoding GLUT9), SLC22A12 (encoding URAT1), SLC17A1 (encoding NPT1) and ABCG2 are most strongly associated with variation in serum urate levels [16].

Other factors affecting serum urate include obesity, mechanism mediating this association has not been determined [17 -19]. Medications can affect serum uric acid levels. Diuretic agents, except potassium-sparing agents (spironolactone) are associated with an increased risk of incident gout [20]. Cyclosporine and low-dose aspirin are well-known factors associated with hyperuricemia, most likely due to their effect on urate renal clearance [21,22].

Additionally, several studies indicated that gut microbiota and their metabolites might contribute to purine and uric acid metabolism. In these studies, lower bacterial diversity and different flora in the gut microbiome are found in gout patients compared to healthy controls [23,24]. Furthermore, differences in key bacterial enzymes related to urate synthesis, degradation, and elimination were observed, which might influence serum urate levels [24].

Monosodium urate crystallization and deposition

Because of the high concentration of sodium in the extracellular compartment, urate is largely present as MSU, and a serum urate level of approximately 6.8 mg/dL is the concentration at which MSU crystals begin to precipitate [4,25].

Hyperuricemia is an essential factor in the development of gout, but not all individuals with hyperuricemia develop gout. About 22% of males with a serum urate level greater than 9.0 mg/dL develop gout within 5 years, and even among individuals with higher serum urate levels (≥10.0 mg/dL), less than half of them develop gout within 15 years [3,26]. In a study that evaluated urate deposits using dual-energy computed tomography (DECT), only 24% of participants with asymptomatic hyperuricemia had urate deposits in joints or tendons detected on DECT [27]. These findings imply that factors other than urate concentration also influence the formation of MSU crystals. Low temperatures, pH 7~9 and high concentration of sodium ions are known factors that reduce urate solubility and promote MSU crystallization [28 -30]. And joints that are damaged, such as those injured or affected by osteoarthritis, tend to have MSU crystal deposition and are more likely to develop gout [30 -32]. Exposure to cartilage matrix proteins or fibers, and lubricin deficiency are the possible mechanisms promoting crystal deposition and enhancing inflammatory responses in damaged joints [30]. MSU can also deposit in extra-articular regions, including the cardiovascular system (especially vessels), kidneys, and spine. This may result in various comorbidities in gout patients [33].

Acute gout flare: the inflammatory response to MSU crystals

1) NLRP3 inflammasome: the pivotal factor in initiating gout inflammation

Some individuals with MSU crystal deposition can progress to develop clinical symptoms of gout, characterized by the rapid onset of a painful, swollen, hot, and red joint [34]. The acute inflammation in gout is a result of the innate immune system’s response to deposited MSU crystals particularly through the activation of the nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasome [35].

The innate immune system typically responds to shared structures from microbes, called pathogen-associated molecular patterns (PAMPs), or from damaged cells, referred to as damage-associated molecular patterns (DAMPs). The receptors for these PAMPs and DAMPs are called pattern recognition receptors (PRRs) and are encoded in the germline, and are not produced by somatic recombination of genes. These PRRs include Toll-like receptors (TLRs), NOD-like receptors (NLRs), C-type lectin receptors (CLRs), retinoic acid-inducible gene I-like receptors (RLRs), and cytosolic DNA sensors (CDSs) [36].

Among them, TLRs are expressed on many cell types, on extracellular or endosomal membranes, and are known to be activated by a variety of PAMPs and DAMPs, including bacterial DNA, lipopolysaccharide (LPS), free fatty acid (FFA), peptidoglycan, viral dsRNA, and fungal zymosan [37].

NLRs are intracellular receptors, and respond to many PAMPs or DAMPs, such as bacterial muramyl dipeptide (MDP), microbial toxins, bacterial or viral RNA, MSU and calcium pyrophosphate dihydrate (CPPD) crystals, and extracellular ATP [37]. When NLRs recognize these activators, they assemble into the inflammasomes, which are large cytoplasmic protein complexes that act as molecular platforms to activate inflammatory caspases [38]. Among NLRs, NLRP3 is the best characterized and is related to MSU induced inflammation [35]. The NLRP3 inflammasome includes the sensor molecule NLRP3, the adaptor protein apoptosis-associated speck-like protein (ASC), and the pro-inflammatory enzyme pro-caspase-1. Additionally, never in mitosis gene A (NIMA)-related kinase 7 (NEK7), a serine-threonine kinase known to be involved in mitosis, was later identified as an essential component of the NLRP3 inflammasome [39]. The assembled NLRP3 inflammasome leads to caspase-1 activation, resulting in the release of the cytokines interleukin-1β (IL-1β) and IL-18, as well as gasdermin D (GSDMD)-mediated pyroptotic cell death [40,41].

2) Priming and activation of the NLRP3 inflammasome in gout

In gout, tissue-resident macrophages recognize MSU crystals as DAMPs and stimulate the activation of NLRP3 inflammasome, leading to the release of active IL-1β, which is the key cytokine in gout inflammation [35].

There are few exceptions, but in most NLRP3 inflammasome-related diseases, including gout, the initiation of the NLRP3 inflammasome in macrophages requires a 2-signal process: priming and activation (Figure 2) [42,43].

In Signal 1, the priming process, that prepares cells for inflammasome assembly, controls the gene expression of pro-IL-1β, which is a bio-inactive precursor, and components of NLRP3 inflammasome through upregulation of transcriptional level and post-translational modification. This process can be induced by various stimuli, such as PAMPs, DAMPs, or cytokines (including tumor necrosis factor [TNF] and IL-1β), through TLRs (particularly TLR2 or TLR4) or cytokine receptors. These signals lead to nuclear factor-κB (NF-κB) activation and gene transcription, resulting in the expression of inflammasome components NLRP3, caspase-1, and pro-IL-1β [42,44 -46].

Several factors are known to activate TLR signaling in gout models. FFA that accumulate due to metabolic alterations such as obesity or fasting, or LPS, which is a microbial product, can trigger TLR2 or TLR4 signaling [47,48]. And Endogenous ligands such as S100A8 (also known as myeloid-related protein 8, MRP-8) and S100A9 (also known as MRP-14), which are secreted by neutrophils and monocytes and elevated in gout patients, can facilitate the activation of TLRs [49].

There is no definitive proof that MSU crystals can directly trigger TLRs. However, a recent study showed that MSU crystals can induce rapid pro-IL-1β production without affecting its mRNA levels, via post-transcriptional regulation through the p38 mitogen-activated protein kinase (MAPK) signaling pathway [50].

In Signal 2, the activation of the NLRP3 inflammasome, phagocytosis of MSU crystals trigger the assembly of the NLRP3 inflammasome complex and the activation of caspase-1 (Figure 2) [37,51]. Caspase-1 then cleaves pro-IL-1β into its active form, IL-1β, which is a key mediator of inflammatory response in gout. The exact mechanisms by which MSU crystals induce NLRP3 activation remain unclear, but ionic K⁺ efflux, Ca²⁺ signaling, lysosomal disruption and mitochondrial reactive oxygen generation are suggested as involved processes [52,53].

Phagocytosis of MSU crystals is required for NLRP3 inflammasome activation in gout, and this uptake induces lysosomal damage and rupture. Lysosomal contents released into the cytosol may be sensed by NLRP3, leading to NLRP3 inflammasome activation [51].

P2X purinoceptor 7 (P2X7R), an ATP-gated cation channel, and two-pore domain weak inwardly rectifying K⁺ channel 2 (TWIK2) appear to play significant roles in ion signaling, particularly in facilitating K⁺ efflux [54 -56]. Transient receptor potential vanilloid 4 (TRPV4), a non-selective mechanosensitive ion channel, is also suggested to play a critical role in MSU crystal-induced NLRP3 inflammasome activation in macrophages. This crystal-induced inflammation is mediated by a neuroimmune interaction between TRPV1-expressing nociceptors and TRPV4-expressing synovial macrophages [57].

Regarding the activation of inflammasome, a recent in vitro study suggested that MSU crystals change the cell circadian clock by reducing BMAL1 and REV-ERBα levels, which are known to regulate inflammation and/or the NLRP3 inflammasome, leading to a loss of NLRP3 inflammasome repression. This may at least partially explain the nocturnal risk of gout flare, suggesting that altered circadian control of immune cell function by MSU crystals in the macrophage circadian clock plays a role [58].

3) Amplification of gout inflammation

Activated IL-1β binds to the IL-1β receptor on target cells and triggers a downstream signaling cascade that activates pro-inflammatory transcription factors. This leads to the upregulation of cytokines and chemokines, resulting in the recruitment of neutrophils and other immune cells to the site of crystal deposition, and gout inflammation [59]. IL-1β inhibitors, such as anakinra, rilonacept, and canakinumab, can be used for patients with severe gout flares or those refractory to or contraindicated for other treatments [60].

Active caspase-1 can also cleave GSDMD, and the amino-terminal fragments of GSDMD (GSDMD N-terminal) oligomerize and form pores in the plasma membrane (Figure 2) [52,53]. These pores facilitate the release of cytosolic cytokines such as IL-1β and lead to cell lysis, a process called pyroptosis [61]. Attracted and activated, neutrophils ingest MSU crystals and eject their chromatin along with cytosolic and granule proteins, resulting in the formation of neutrophil extracellular traps (NETs). This process is called NETosis [62]. Neutrophil-derived serine proteinases, such as neutrophil elastase, cathepsin G, and proteinase-3, can also process pro-IL-1β into mature IL-1β, in an inflammasome-independent manner, amplifying the inflammatory response [63].

The resolution of inflammation

One of the characteristic features of acute gouty arthritis is its self-limiting nature. Neutrophils recruited to the site of inflammation also play a role in the resolution of inflammation. At low neutrophil cell densities, neutrophil induce the formation of proinflammatory NETs and release cytokine and chemokine. But under high neutrophil densities, these NETs aggregate. These aggregated NETs (aggNETs) trap and degrade cytokines and chemokines through NET-bound proteases, promoting the resolution of inflammation [62].

Besides aggNETs, IL-33, IL-37, IL-1 receptor antagonist, and transforming growth factor β1 (TGF-β1) are associated with relieving gout inflammations by inhibiting the action of the IL-1β pathway [64].

Advanced gout

Advanced gout is characterized by tophi, chronic inflammatory responses, and structural joint damage [59]. Tophi usually appear clinically in people with a longer duration of gout (at least 10 years) and higher serum uric acid levels [65]. Tophi are commonly found in articular, periarticular, and subcutaneous areas such as joints, bone, cartilage, tendons, and skin. Uncommonly, tophi may be found in spine and parenchymal organs as well [66]. However, in some individuals with gout, tophi can occur earlier in the disease, especially in those who have decreased creatinine clearance [67]. Although tophi primarily consist of MSU crystals, they are complex structures. Microscopically, tophi is chronic foreign body granuloma-like structures containing collections of MSU crystals encased by inflammatory cells and connective tissue, that can be distinguished into three zones. The central zone contains dense MSU crystals, while surrounding this central zone is the corona zone, which consists of macrophages, plasma cells, T and B lymphocytes, and mast cells. This zone is a key in the inflammatory response. And the corona and central zones may become encased by a connective tissue layer, the fibrovascular zone [68]. Within a tophus, a chronic inflammatory reaction typically occurs, involving both the innate and adaptive immune systems. There is coexpression of both pro- and anti-inflammatory factors such as IL-1β and TGF-β1. These findings suggest that there is a cycle of chronic inflammation, attempted resolution, and tissue remodeling [69].

There is a close relationship between the presence of tophi and structural damage in joints affected by gout. Tophi are usually present at sites of structural damage in gout. A quantitative analysis for bone erosion on plain radiography and tophi on CT showed strong relationship between bone erosion and the presence of intraosseous tophus [70]. A MRI also has shown that tophi, but not bone marrow edema or synovitis, is independently associated with the presence of bone erosion [71]. At the interfaces of tophi and bone, numerous osteoclasts can be found, indicating a relationship between tophi and osteoclastogenesis [72]. The differentiation and maturation of osteoclasts are largely regulated by macrophage colony-stimulating factor (M-CSF), receptor activator of NF-κB ligand (RANKL), and osteoprotegerin (OPG) [73]. Macrophages in tophus produce IL-1β, TNF, IL-6, IL-17, matrix metalloproteinases (MMP)-2, and MMP-9, and M-CSF, these molecules induced inflammations and osteoclastogenesis [74,75]. T cells within tophus also promote bone erosion through the expression of RANKL, which is a major promoter of osteoclastogenesis and osteoclast activation [75]. MSU crystals inhibits gene expression of OPG, a negative regulator of osteoclastogenesis, in stromal cells, leading to an alteration of the RANKL to OPG ratio, favoring the differentiation of precursor cells into mature osteoclasts and thus increasing bone resorption [72]. MSU crystals and macrophages within tophus also affect osteoblasts by attenuating viability and differentiation of osteoblast and inducing expression and secretion of proinfammatory mediators from osteoblasts [76,77]. Additionally, the function of osteocytes is shifted to favor bone resorption and inflammation with MSU crystal-stimulated macrophages [78]. Chondrocytes can be affected by MSU crystals, which reduce their viability and promote a catabolic state. This includes a decreased expression of matrix proteins and an increased expression of degradative enzymes, leading to cartilage damage [79].

CONCLUSION

Gout is the most common inflammatory arthritis in adults, associated with hyperuricemia and the deposition of MSU crystals. Hyperuricemia arises from increased uric acid production or decreased excretion by kidneys and intestines, regulated by urate transporters. Genetic variations in these transporters influence serum urate levels. The inflammatory response to MSU crystals is mediated by the NLRP3 inflammasome, which activates IL-1β, leading to cytokine and chemokine upregulation, attracting immune cells. Neutrophils contribute to inflammation resolution by forming aggNETs that degrade cytokines. Advanced gout is characterized by tophi, chronic inflammatory responses, and structural joint damage.

ACKNOWLEDGMENTS

None.

Notes

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

E.A. and M.W.S. drafted the manuscript and reviewed the draft manuscript. All authors approved the final manuscript.

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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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