The biology of urate.pdf

Seminars in Arthritis and Rheumatism 50 (2020) S2 S10 Contents lists available at ScienceDirect Seminars in Arthritis and Rheumatism journal homepage: www.elsevier.com/locate/semarthrit The biology of urate Robert T. Keenan Division of Rheumatology, Duke University School of Medicine, Durham 27710, NC, USA A B S T R A C T Urate is the end-product of the purine metabolism in humans. The dominant source of urate is endogenous purines and the remainder comes through diet. Approximately two thirds of urate is eliminated via the kidney with the rest excreted in the feces. While the transporter BCRP, encoded by ABCG2, has been found to play a role in both the gut and kidney, SLC22A12 and SLC2A9 encoding URAT1 and GLUT9, respectively, are the two transporters best characterized. Only 8 12% of the ﬁltered urate is excreted by the kidney. Renal elimination of urate depends substantially on speciﬁc transporters, including URAT1, GLUT9 and BCRP. Studies that have assessed the biologic effects of urate have produced highly variable results. Although there is a suggestion that urate may have anti-oxidant properties in some circumstances, the majority of evidence indicates that urate is pro-inﬂammatory. Hyperuricemia can result in the formation of monosodium urate (MSU) crystals that may be recognized as danger signals by the immune system. This immune response results in the activation of the NLRP3 inﬂammasome and ultimately in the production and release of interleukin-1b, and IL-18, that mediate both inﬂammation, pyroptotic cell death, and necroinﬂammation. It has also been demonstrated that soluble urate mediates effects on the kidney to induce hypertension and can induce long term epigenetic reprogramming in myeloid cells to induce “trained immunity.” Together, these sequelae of urate are thought to mediate most of the physiological effects of hyperuricemia and gout, illustrating this biologically active molecule is more than just an “end-product” of purine metabolism. © 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/) Introduction The metabolic production of uric acid is ubiquitous amongst animals and other life forms. It is important to recognize that urate can have both beneﬁcial and pathological roles in human physiology. Uric acid (C5H4N4O3) is a heterocyclic organic compound with a molecular weight of 168 Da. It is synthesized from the metabolism of the purine nucleic acids, adenine and guanine. In this process, adenosine monophosphate is converted to inosine and guanine monophosphate is converted to guanosine. These two nucleosides are then converted to hypoxanthine and guanine. Hypoxanthine is oxidized to form xanthine by xanthine-oxidase, and guanine is deaminated to form xanthine by guanine deaminase. Xanthine is again oxidized by xanthine oxidase to form uric acid. At physiologic pH, uric acid in the body exists mainly as urate [1]. The normal reference range for urate in human blood is 1.5 to 6.0 mg/dL in women and 2.5 7.0 mg/dL in men. When the level of urate is >6.8 mg/dL (405 mmol/l), the limit of solubility under physiological conditions, crystals of urate may form as monosodium urate (MSU) [1]. Multiple factors Publication of this supplement was supported by Horizon Therapeutics plc. E-mail address: [email protected] have been found to inﬂuence MSU crystal formation, including temperature, sodium and cation concentration, pH, mechanical stress, cartilage components, uric acid binding antibodies, and components of cartilage and synovial ﬂuid [2,3] (Fig. 1). It is important to understand and appreciate that physiological conditions are not always at ideal clinically, and crystal formation and deposition can occur at levels between 6 and 7 mg/dL. Therefore, 6 mg/dL (360 mmol/l) should be seen as the limit of solubility in both female and male patients. Humans, some higher primates, and certain New World monkeys do not show any detectable uricase activity [4,5]. Urate is maintained in humans and higher primates because of the loss of uricase activity resulting from various mutations of its encoding gene during the Miocene epoch. At ﬁrst glance, uric acid or urate seems to be just metabolic waste needing excretion, but some studies implicate otherwise. It has been suggested that there may be beneﬁts to the absence of uricase and high urate levels. These may include antioxidant activity, better maintenance of blood pressure in times of low salt ingestion, and changes in fructose metabolism [4]. Some studies have demonstrated that uric acid is a major immunological adjuvant or ‘danger’ signal found in damaged cells, and that it alone could promote T cell activation [6]. Additionally, the uric acid danger signal may play a role in tumor immunity [7]. This https://doi.org/10.1016/j.semarthrit.2020.04.007 0049-0172/© 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/) R.T. Keenan / Seminars in Arthritis and Rheumatism 50 (2020) S2 S10 Clinical manifestation Disease progression Risk factor or cause Asymptomatic state No disease Normouricaemia Hyperuricaemia • Genetic factors (e.g. SNPs in urate transporter genes) • Environmental factors (e.g. diet and BMI) • Impaired kidney function • Increasing age • Male sex • Medications • High cell turnover states, etc. Symptomatic disease MSU crystal deposition • Reduced solubility of urate • Increased nucleation of MSU crystals • Growth of MSU crystals Recurrent gout flares Acute inflammatory response to deposited MSU crystals S3 Symptomatic disease with complications Chronic gouty arthritis and tophaceous gout Chronic granulomatous inflammatory response to deposited crystals Fig. 1. Disease progression and risk factors. potential role of uric acid will be further discussed in the section addressing pain and Inﬂammation associated with MSU crystals. is a substantial contributor to extra-renal elimination of urate. Importantly, ABCG2 polymorphisms have been found to be associated with early onset gout in patients less than 30 years old [20,21]. Elimination of urate Deﬁnition of hyperuricemia The production and catabolism of purines are relatively constant between 300 and 400 mg per day and about two-thirds of the urate produced by these products is eliminated via the kidney, and the rest is eliminated by the gastrointestinal tract [1,8,9]. In healthy, fully functioning nephrons, this process is responsive to serum urate levels resulting in increased renal excretion with rises in serum urate. Urate is almost completely unbound by plasma proteins, therefore nearly all urate undergoes ultraﬁltration by glomeruli. Subsequent to ﬁltration by the glomeruli, urate enters the S1 segment of the proximal tubule where it undergoes resorption, resulting in a net reclamation of between 90% and 98%. At the distal proximal tubule, secretion occurs in which resorbed urate is transported into the tubule lumen resulting in approximately 10% of the ﬁltered urate being excreted in the urine and 90% is reabsorbed [1,10,11]. Three transporters, URAT1, GLUT9, and BCRP, have been reported to play important roles in the elimination and regulation of urate [1,12 16] (Fig. 2). URAT1 is the most important apical urate exchanger in the proximal tubule and it plays a key role in the physiology of urate homeostasis. The URAT1 protein is encoded by the SLC22A12 gene. GLUT9 (SLC2A9), and is responsible for the basolateral transport of urate in the proximal tubule. ABCG2 is one of three human adenosine triphosphate (ATP) binding cassette (ABC) transporters, and it is involved in the cellular export of a larger number of chemically and structurally diverse compounds. It has been shown to play a signiﬁcant role in renal and gastrointestinal urate excretion. Additional studies have shown the importance of organic anion transporters (OAT) in both the retention and elimination of urate from the kidney. Interestingly, recent studies have shown a potential uricosuric effect of a sodium-glucose transporter 2 (SGLT2) inhibitor which raises the possibility of urate transport across the SGLT2 [17]. Almost six decades ago, Sorensen reported that in healthy individuals the gut is responsible for 20 30% of the urate that is eliminated daily [18]. Despite the role of the gut being recognized for its role in urate homeostasis for over 50 years, the mechanism in extra-renal elimination of urate is still not completely understood. A study in rats showed that signiﬁcant amounts of externally administered and endogenous urate were recovered in the intestinal lumen with minimal biliary excretion [8]. Additional experiments showed that the efﬂux transporter, ABCG2 contributes to the intestinal excretion of urate [19]. Although still under appreciated, these results support the view that direct intestinal secretion Hyperuricemia is deﬁned as a serum urate concentration >6.8 mg/ dL (the in vitro solubility limit of MSU). Gout typically emerges in individuals with serum urate >6.8 mg/dL (360 mmol/L) and its prevalence rises with increases in serum urate above this threshold [22,23]. Guidelines recommend lowering serum urate to <6 mg/dL (360 mmol/l), the level clinically seen as the limit of solubility, as deposition can occur at levels around 6.8 mg/dL in vivo as noted above. The guidelines also note some patients should be treated more aggressively to target serum urate levels below 5 mg/dL (mmol/ L) (i.e., patients with higher urate burden and disease severity, often manifested by the presence of clinically evident tophi, recurrent ﬂares, and signiﬁcant disability) [24]. Development of hyperuricemia Dietary factors Dietary factors have been demonstrated to play a signiﬁcant role in the development of hyperuricemia [9,25]. Excess consumption of alcohol and purine-rich foods (e.g., meats, seafood, some vegetables, and animal protein) have been implicated in the development of hyperuricemia since urate is the end product of purine degradation. Results from the Third National Health and Nutrition Examination Survey (NHANES III) indicated that higher levels of meat and seafood consumption were associated with higher serum urate levels, but that total protein intake was not [26]. Dairy consumption was inversely associated with serum urate concentrations. Sir William Osler implicated sugar intake as a risk for gout [27]. Over a century later, NHANES data indicated an increase in urate of 0.33 mg/dL in participants drinking 1 3.9 sugar-sweetened servings per day vs participants drinking none after adjustment for diet including total energy intake, age, sex, medications, hypertension, and estimated glomerular ﬁltration rate (eGFR) [28]. Results from the Cross-Sectional Analysis from the Brazilian Longitudinal Study of Adult Health also indicated that consumption of soft drinks and dietary fructose is positively associated with hyperuricemia and higher urate levels in Brazilian adults [29]. Other studies addressing this issue have conﬁrmed this relationship, but the association was weak S4 R.T. Keenan / Seminars in Arthritis and Rheumatism 50 (2020) S2 S10 Fig. 2. Urate transporters. [30 32]. The relationship makes physiological sense given the metabolism of fructose compared to sucrose results in the generation of additional substrates (AMP) for uric acid generation, but prospective studies are needed to improve our understanding of the role of fructose in the development of hyperuricemia and gout [33]. Although social and medical dogma dictate the importance of diet in urate formation and subsequently gout (particularly gout ﬂares), a recent meta-analysis has challenged the absolute role purine intake plays in hyperuricemia. In a study of almost 17,000 individuals of European descent, Major and colleagues did ﬁnd an association between dietary intake of alcohol, meats, and soft drinks with hyperuricemia, and an inverse relationship with skim milk, eggs, cheese and non-citrus fruits [34]. These ﬁndings were consistent with other diet and hyperuricemia studies, but interestingly, they found the role of diet contributing to no more than 0.3% of the variance in serum urate levels. Conversely, they found 23.9% of the variance in serum urate levels was explained by genome wide single nucleotide variation. This study not only illuminates the role diet and environmental factors play in serum urate levels, but also the factor we cannot control, genetics. UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4. These include genes that encode transporters, transcriptional factors, signaling receptors, and enzymes [25,40,41]. It is important to note that not all individuals with hyperuricemia develop gout (i.e., symptomatic hyperuricemia) and that some people with high urate levels remain asymptomatic [42]. Genetic factors have been implicated in the transition from hyperuricemia to gout. A multistage genome-wide association study (GWAS) resulted in the discovery of three loci,17q23.2 (rs11653176, BCAS3), 9p24.2 (rs12236871, RFX3) and 11p15.5 (rs179785, KCNQ1) containing inﬂammatory candidate genes that appear to be related to progression from hyperuricemia to inﬂammatory gout [43]. A second GWAS demonstrated three loci (CNTN5, MIR302F, and ZNF724) associated with mechanisms of gout development, which differ from the known gout risk loci that elevate serum urate levels. CNTN5 is a member of the contactin family and it is associated with inﬂammatory diseases including ankylosing spondylitis and Behçet’s disease. The microRNA MIR302F also appears to be involved in cancer; and, the exact function of ZNF724 is not known [44]. Genetic factors Anti-inﬂammatory and pro-inﬂammatory actions of urate Multiple genetic factors contribute to the development of hyperuricemia. Genome-wide association studies have identiﬁed multiple loci associated with the development of hyperuricemia. Polymorphisms and mutations in the genes SLC22A12, SLC2A9, and ABCG2 encoding, the previously described transporters (URAT1, GLUT9, and BCRP, respectively) have been implicated in the development of hyperuricemia and gout [35 38]. Other important genes implicated in hyperuricemia and gout include: SLC22A11, encoding OAT4; SLC17A1, encoding NPT1, SLC17A3, encoding NPT4; PDZK1, encoding PDZ domain containing 1 scaffolding protein involved in assembly of urate transportasome; and GCKR, encoding glucokinase regulator (regulatory protein inhibiting glucokinase in the liver and pancreas) [39]. Other loci that have been associated with variations in serum urate concentrations include regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, It has been suggested that urate acts as a free radical scavenger, and is considered one of the most important natural anti-oxidants in humans [45,46]. The anti-oxidant effects of urate prompted exploration of neuroprotective effects of urate. Multiple beneﬁcial actions have been suggested on the basis of results from studies in animals and administration of urate also appears to improve cognitive function in patients with intellectual disability [47,48]. The mechanism by which urate positively impacts neurological function includes suppression of oxygen radical accumulation, stabilization of calcium homeostasis, preservation of mitochondrial function, and protection of neurons from glutamate-associated toxicity. Urate has been posited as neuroprotective in several diseases including stroke, Parkinson’s disease (PD), multiple sclerosis (MS) and Alzheimer’s disease (AD). The presence of high circulating levels of urate has been related with lower severity of neurological damage R.T. Keenan / Seminars in Arthritis and Rheumatism 50 (2020) S2 S10 and lower volume of cerebral infarction in patients with stroke [49]. Urate administration during the course of acute ischemic stroke is associated with smaller cerebral ischemia [47]. The URICO-ITCUS study, a randomized, double-blinded, placebo-controlled phase 2b/3 trial evaluating 411 patients with acute stroke showed adding a 1000 mg intravenous uric acid to thrombolytic therapy did not increase the proportion of patients achieving excellent outcomes (deﬁned as a modiﬁed Rankin Scale score of 0-1, or 2 if premorbid score was 2) [50]. However, further analysis of this study showed the uric acid group had less early ischemic worsening compared to placebo, especially in patients with good collateral circulation [51]. High serum urate levels have been associated with reduced risk for development of PD and slower progression in patients diagnosed with PD and multiple sclerosis [52 55]. Epidemiologic studies suggest hyperuricemia may have a protective effect against Alzheimer’s disease [56]. Further support for this observation was demonstrated by a prospective study following patients with mild dementia [57]. The author’s found patients in the lowest serum urate quintile had a signiﬁcantly greater progression of cognitive decline, compared with those in the highest quintile over a 36-month period. In a murine MS model, there was a dose dependent relationship between high uric acid levels and progression of disease [58]. However, attempts to slow MS progression by administering inosine to raise urate levels have not been effective and this treatment also increased the risk for renal complications [59,60]. In contrast, a recent meta-analysis showed inconsistent effects and may differ depending whether dementia is of the vascular or AD type [61]. Other studies have seen similar results regarding the impact of hyperuricemia, speciﬁcally on vascular dementia [62]. To muddle the impact of urate on dementia, urate lowering therapy (ULT) seemed to decrease the risk of dementia in gout patients [63]. Contrary to the data supporting urate’s anti-inﬂammatory effects, urate has been found to be a pro-oxidant by forming radicals in reactions with other oxidants, and these radicals seem to target predominantly lipids (e.g., low density lipoproteins) [46]. Urate may also interfere with normal endothelial function by inhibition of nitric oxide (NO) function under conditions of oxidative stress [64]. Additionally, urate has been shown to increase in NADPH oxidase activity and reactive oxygen species (ROS) production in mature adipocytes. The stimulation of NADPH oxidase-dependent ROS by urate has been shown to activate mitogen-activated protein kinase p38 and ERK1/2, decrease NO bioavailability, and increase protein nitrosylation and lipid oxidation [65]. Facilitating the counterargument to urate being anti-inﬂammatory, it has been noted that the anti-inﬂammatory actions of urate are modest. A study in rats indicated that urate was unlikely to play an important role in protecting neurons by quenching oxygen radicals [66]. Other studies have suggested that urate may not have substantial anti-oxidant effects. Oxidative stress has been assessed by measurement of F2-Isoprostanes (F2-IsoPs) and protein carbonyls (PC); and lowering urate levels to 1 mg/dL in patients with refractory gout by administration of pegloticase did not change concentrations of either F2-IsoP or PC. The authors of this study concluded that urate is not a major factor controlling oxidative stress in vivo [67]. Additional studies have either failed to demonstrate a neuroprotective effect of urate in humans and/or suggested adverse actions. A longitudinal study in 1598 healthy elderly people showed that the risk of dementia, particularly vascular or mixed dementia, may be increased with high serum urate levels [64]. However, a systematic review and meta-analysis indicated inconsistent relationships between all types of dementia and serum urate levels [68]. Evidence related to a potential anti-oxidant and organ-protective effect of urate, and thus a potential risk of urate lowering, are mixed and the limited prospective data available provides no clear support. Conversely, the pro-inﬂammatory effects of urate may outweigh the potential anti-inﬂammatory effects, particularly when above the limit S5 of solubility (>6.8 mg/dL). Hyperuricemia and its pro-inﬂammatory effect has been linked to adverse metabolic, cardiovascular, and renal effects. Consequences of hyperuricemia Metabolic effects Higher serum urate levels have been shown to be associated with increased risk for the development of diabetes [37,69] and the metabolic syndrome [70 72]. High serum urate is also associated with elevated body mass index, hypercholesterolemia, hypertriglyceridemia, increased fasting plasma glucose, and insulin resistance [73 75]. This consistent evidence has illuminated the dose effect of urate on the risk for metabolic syndrome, and subsequently may contribute to the adverse cardiovascular effects of elevated urate levels [76,77]. Cardiovascular effects There are well-known adverse cardiovascular effects of elevated serum urate levels [78]. Results from multiple observational studies have demonstrated signiﬁcant associations between hyperuricemia and hypertension [79], cardiovascular and cerebrovascular events [80 84], and heart failure [85]. It has been speculated that elevated serum urate may contribute to cardiovascular disease via multiple mechanisms, including impaired NO production/endothelial dysfunction, increased vascular stiffness, elevated oxidative stress, endothelial cell apoptosis, and vascular, cardiac, and renal ﬁbrosis [86 91]. A small number of prospective interventional studies have provided evidence that lower urate levels may decrease cardiovascular risk. It has been shown that administration of allopurinol in patients with chronic kidney disease decreased C-reactive protein, slowed the progression of renal disease, and reduced the risk for cardiovascular events [92]. It has also been demonstrated that treatment with febuxostat prevents arterial stiffening as measured by pulse wave velocity in patients with severe chronic refractory tophaceous gout [93]. Additionally, there is some evidence pegloticase and subsequent urate lowering effects decreases blood pressure in patients with chronic refractory gout, although further studies are needed to further support this [94]. Hypertension Results from multiple analyses have demonstrated a strong association between elevated urate levels and hypertension. A meta-analysis that included 25 studies (97,824 participants) indicated that hyperuricemia was associated with a signiﬁcantly elevated risk for incident hypertension [95]. Similar results were reported in an earlier meta-analysis of 18 prospective cohort studies representing data from 55,607 participants [79]. Results from several studies, including adolescents and adults, have demonstrated that lowering serum urate with xanthine oxidase inhibitors and uricosurics in patients with either asymptomatic hyperuricemia or gout also decreases blood pressure [94,96 100]. Conversely, a recent study evaluating overweight and obese hypertensive patients with probenecid and allopurinol did not show any signiﬁcant change in endothelial function or mean blood pressure [101]. It is important to recognize this patient population was not signiﬁcantly hyperuricemic and whose mean serum urate was 6.1 mg/dL + 0.9 mg/ dL, thus possibly impacting the results in comparison study populations with a higher baseline serum urate level. Renal effects Elevated urate levels have been associated with a large number of changes in renal structure and function. Urate signiﬁcantly increases toll-like receptor (TLR) 4, NOD-like receptor family pyrin domain containing 3 (NALP3), caspase-1, interleukin (IL) 1b, and S6 R.T. Keenan / Seminars in Arthritis and Rheumatism 50 (2020) S2 S10 intercellular adhesion molecule-1 expression in the human primary renal proximal tubule epithelial cells [102]. Urate also decreases the expression of E-cadherin in epithelial cells resulting in a loss of cellto-cell contact among renal tubular cells and decreased secretion of substances (e.g., NO) that increase renal blood ﬂow [103]. Elevated urate can also lead to endothelial dysfunction, vascular smooth muscle cell proliferation, and increased IL-6 synthesis, all of which may contribute to the progression of chronic kidney disease (CKD) [104]. Patients with CKD stages 3 5 have higher serum urate levels that are associated with elevated systolic blood pressure, higher C-reactive protein levels, lower glomerular ﬁltration rate, and lower ﬂow-mediated dilatation [105]. Elevated serum urate has also been correlated with worsening renal function irrespective of age, gender, race, diabetes, hypertension, alcohol use, smoking, lipids, and baseline renal function [106]. A retrospective study including 12,751 patients with CKD stage 2, 3, and 4 and serum urate levels > 7 mg/dL over an 8-year period evaluated the impact of urate lowering on progression of CKD [107]. Of the 2690 patients on urate lowering therapy, 42% achieved a target serum urate of < 6 mg/dL. Those with CKD stage 2 and 3 achieving a target of < 6 mg/dL were 30% more likely to see an improvement in eGFR, while no difference was seen in patients with CKD stage 4. The evidence from in vitro, ex vivo, epidemiological and even some clinical studies have shown an effect of urate lowering on kidney function, but prospective evidence of intervention and slowing the progression of chronic kidney injury is limited. In a randomized, double-blinded, placebo-controlled trial, Kimura and colleagues evaluated the effects of febuxostat and lowering serum urate on the slope of the eGFR in asymptomatic hyperuricemia patient with stage 3 CKD [108]. After two years of follow-up, the study found no signiﬁcant difference between the febuxostat group and placebo group, but it is noteworthy the placebo group only had a 1% decline in eGFR. This trial and similar trials have only included low risk patients that may not have had signiﬁcant progression regardless, as noted by the placebo group [109]. Additional studies need to include higher-risk cohorts to have the statistical power and better evaluate the impact of lowering serum urate on kidney function decline. A subsequent study aimed to compare allopurinol and febuxostat versus standard of care, evaluating CKD stage 3 patients who were hyperuricemic (deﬁned as > 7 mg/dL) [110]. Forty patients received allopurinol with a mean dose of 164 mg, 30 patients received febuxostat with a mean dose of 55 mg, and 71 patients received standard treatment. Over the course of the observation period that ranged from 24 to 87 months, the febuxostat group had signiﬁcantly lower mean serum urate compared to both allopurinol and control, maintained a higher mean eGFR, and had a longer renal survival time free from disease progression. Although this study contradicts the ﬁndings of the aforementioned study, it begs the question of whether or not treating to target in both the febuxostat and allopurinol groups would have resulted in positive results in both groups. Fig. 3. Sequence of monosodium urate crystallization Adapted from Martillo MA et al. Curr Rheumatol Rep. 2014; 16:400. ]2]. Formation of MSU crystals, inﬂammation, and organ damage The process of MSU crystallization is similar to that for the formation of other crystals, and is thought to depend on both urate concentration and other factors (Fig. 3). It has been suggested that MSU remains in solution until an event that changes solubility (e.g., increased concentration and decreased temperature). This results in clustering of MSU molecules while still in solution. These clusters aggregate into crystal nuclei, providing the basis for additional crystal formation and growth. Local factors may promote nucleation and crystal growth (e.g., low pH, elevated calcium levels, organic molecules originating from cartilage or the synovium, albumin, antibodies, sodium ions) [2,3]. MSU crystal formation Pain and inﬂammation associated with MSU crystals Although the presence of hyperuricemia is essential for the formation of MSU crystals, only a fraction (2 6%) of hyperuricemic patients develop clinical gout. This may result from a variable biologic response to elevated urate or inadequate detection of the disease. Conversely, some patients have normal serum urate (6.0 mg/dL) at the time of an acute gout attack, indicating that the relationship between serum urate level and acute MSU crystallization is complex [2,111]. Urate levels decrease during an acute attack [112], possibly secondary to the uricosuric effects of inﬂammatory mediators and hormone production, such IL-6 and adrenocorticotropic hormone, respectively. MSU crystals activate a speciﬁc inﬂammatory cascade in leukocytes leading to production of IL-1 and IL-18 [113 117]. The innate immune system recognizes and responds to pathogens and to endogenous molecules released by host cells via detection of pathogenassociated and danger-associated molecular patterns (PAMPS and DAMPs respectively). The inﬂammation MSU crystals induce has been revealed to be more complex than initially appreciated. MSU crystals cause the release of reactive oxygen species and reactive nitrogen species are released from ﬁbroblasts and ﬁbroblast-like synoviocytes causing cell death [118]. In vitro studies have also shown R.T. Keenan / Seminars in Arthritis and Rheumatism 50 (2020) S2 S10 that MSU crystals (in addition to calcium pyrophosphate, calcium oxalate, and cysteine crystals) can cause direct cytotoxicity, inﬂammation, and inﬂammation-driven cytotoxicity. This crystal-induced inﬂammation is referred to as necroinﬂammation [118]. Necrotic cells release stimulatory molecules such as DAMPs, IL-1a, and other alarmins fueling the recruitment of innate immune cells such as neutrophils and macrophages into the synovium and surrounding soft tissue [119]. This response is mediated by pattern-recognition receptors that include TLRs, intracellular RIG-like helicases, and NOD-like receptors (NLRs). NLRs respond to PAMPs/DAMPs through the formation of the NLRP3 inﬂammasome. These are multimeric cytoplasmic protein complexes which act as molecular platforms for the activation of inﬂammatory caspases following stimulation by foreign agonists. A typical inﬂammasome is composed of an NLR, an adaptor protein such as apoptosis-associated specklike protein containing a CARD and an effector caspase that activates proinﬂammatory cytokines, in particular IL-1b. MSU crystals (and uric acid) may act as a ‘danger’ signal to cells in a similar way to microbial pathogens and result in the activation of inﬂammasomes [118,120,121]. Caspase-1 cleaves pro-IL-1b and pro-IL-8 to generate IL-1b and IL-18, permitting the release of these cytokines into the extracellular space [114,122]. Once secreted, IL-1b leads to production of other chemokines and cytokines, resulting in the recruitment of leukocytes. Intracellular IL-1b signals for inﬂammation via activation of nuclear factor-kB (NFkB) and other inﬂammatory molecules [123,124]. While IL-1b is recognized as the chief cytokine in gout, both IL-1a and IL-8 may also play important roles in initiating inﬂammatory cascades in this disease [125]. Pain associated with MSU crystal deposition is mediated by several inﬂammatory substances that are formed after cell injury by crystals [126]. These molecules (prostaglandins, bradykinin, cytokines, substance P, transient receptor potential ankyrin 1) exert their effects through different receptor subtypes present in both peripheral sensory neurons and the spinal cord [127]. An important issue in considering the pain associated with gout is the variability in timing, extent, and duration of acute inﬂammatory responses in patients with this disease. Advanced imaging methods (i.e., high resolution ultrasound and highly S7 speciﬁc dual energy computed tomography) have shown that patients with MSU crystal deposits may remain asymptomatic and a large number of factors, such as long-chain fatty acids, complement, kinins, microRNA, IL-37, and neutrophil microvesicles may inﬂuence clinical expression of MSU crystal accumulation (Fig. 4) [128]. MSU crystals and inﬂammation in speciﬁc organ systems Joints: acute versus chronic joint pathology There is a close relationship between MSU crystal deposition and joint damage. In people with advanced gout, bone erosion is a frequent ﬁnding on plain radiography. In addition, other structural damage including joint space narrowing and features of new bone formation, such as bone sclerosis and spur formation, are frequently observed [129]. Factors contributing to joint damage include receptor activator of NFkB ligand (RANKL) expressing osteoclasts and T cells present within gouty tophus tissues, and inﬁltrating cells express inﬂammatory cytokines such as IL-1, IL-6, and tumor necrosis factora [130]. MSU crystals may also interact with articular tissues to inﬂuence the development of structural joint damage [131]. It has also been shown that MSU crystals decrease osteocyte viability and, through interactions with macrophages, promote a shift in osteocyte function that increases bone resorption and inﬂammation [132]. MSU crystals also may cause the death of chondrocytes via autophagy and/ or endoplasmic reticulum stress [133]. Cardiovascular system Silent deposits of MSU crystals are associated with more severe coronary calciﬁcation [134]. Dual energy computed tomography has demonstrated MSU deposition in the aortas and coronary arteries of patients with gout [135]. However, an epidemiologic study indicated that the presence of MSU crystals did not seem to result in further elevation of the already increased cardiovascular risk in hyperuricemic patients [136]. Fig. 4. Inﬂammatory responses to urate crystal deposits Adapted from Terkeltaub R. BMC Medicine 2017;15:158. [128]. S8 R.T. Keenan / Seminars in Arthritis and Rheumatism 50 (2020) S2 S10 Kidney Results from an in vitro study supported the conclusion that oxidative stress generated by MSU crystals promotes renal apoptosis through the mitochondrial caspase-dependent apoptosis pathway [137]. Another in vitro study indicated that MSU crystals are cytotoxic to renal cells and this cytotoxicity involves necroptosis as a form of regulated cell death in vitro and in vivo [138]. Results from in vitro studies of human embryonic kidney cells have shown that MSU crystals promote expression of reactive oxygen species, inducible nitric oxide synthase, and cyclo-oxgenase 2. In addition, enhanced caspase expression stimulated by MSU crystals resulted in renal cell apoptosis [137]. It has also been shown that incubation of MSU with human renal mesangial cells (HRMCs) increases intercellular adhesion molecule-1 expression and subsequent cell cell adhesion between HRMCs and monocytic cells. Inﬁltration of monocytes into the glomerular mesangium contributes to the development of glomerulonephritis [139]. Resolution of acute crystal induced inﬂammation Although chronic low grade inﬂammation is thought to be incited by the presence of MSU crystals, acute crystal induced inﬂammation, the gout ﬂare, can begin to resolve in a few days, and typically resolves in less than 2 3 weeks without intervention. That said, without a counter response from the immune system itself, a cytokine storm could result [118]. The immune system is able to dampen the inﬂammation of a gout ﬂare despite the nidus of the ﬂare, the MSU crystal, still being present. Just as the inﬂammatory process is complex, so is its resolution. There are multiple factors and mediators in the involvement of the dampening of MSU crystal induced inﬂammation. The switching of pro-inﬂammatory to anti-inﬂammatory macrophages have been surmised to play a role [140]. Also, typical anti-inﬂammatory mediators of the immune system such as transforming growth factor beta (TGF-b), IL-10, IL-37, and melanocortin are implicated in acute gouty inﬂammation resolution [141 144]. Schauer and colleagues have shown that once the inﬂammatory process approaches crescendo, speciﬁcally, an abundance of neutrophils recruited to the site of inﬂammation, neutrophil extracellular traps (NETs) form, dampening of the inﬂammatory response and facilitating ﬂare resolution [145]. Analysis of tophi have revealed extracellular DNA to be in direct contact with MSU crystals. The ingestion of MSU crystals by neutrophils causes cell death and rapid extrusion of cellular DNA results in NET formation, or NETosis. As the number of neutrophils are recruited, the NETs increase and cluster the crystals, forming aggregated NETs (aggNETs) [144]. This packaging of crystals and tophi formation is thought to be the tipping point from inﬂammation to resolution of a gout attack [144]. Functional studies using NETs have also shown their ability to quickly absorb, trap, cleave and degrade inﬂammatory mediators, thereby removing the fuel to the ﬁre [145]. Conclusions The balance of urate formation and excretion is driven by multiple enzymatic pathways and genetic studies have suggested that multiple genetic polymorphisms may inﬂuence uric acid excretion. Urate has both pro- and anti-inﬂammatory effects. 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Innate immunity conferred by Toll-like receptors 2 and 4 and myeloid differentiation factor 88 [121] [122] [123] [124] [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] [135] [136] [137] [138] [139] [140] [141] [142] [143] [144] [145] expression is pivotal to monosodium urate monohydrate crystal-in

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