Monosodium Urate Research Articles

Functional identification of soluble uric acid as an endogenous inhibitor of CD38

Excessive elevation or reduction of soluble uric acid (sUA) levels has been linked to some of pathological states, raising another subject that sUA at physiological levels may be essential for the maintenance of health. Yet, the fundamental physiological functions and molecular targets of sUA remain largely unknown. Using enzyme assays and in vitro and in vivo metabolic assays, we demonstrate that sUA directly inhibits the hydrolase and cyclase activities of CD38 via a reversible non-competitive mechanism, thereby limiting nicotinamide adenine dinucleotide (NAD+) degradation. CD38 inhibition is restricted to sUA in purine metabolism, and a structural comparison using methyl analogs of sUA such as caffeine metabolites shows that 1,3-dihydroimidazol-2-one is the main functional group. Moreover, sUA at physiological levels prevents crude lipopolysaccharide (cLPS)-induced systemic inflammation and monosodium urate (MSU) crystal-induced peritonitis in mice by interacting with CD38. Together, this study unveils an unexpected physiological role for sUA in controlling NAD+ availability and innate immunity through CD38 inhibition, providing a new perspective on sUA homeostasis and purine metabolism.

Functional identification of soluble uric acid as an endogenous inhibitor of CD38.

Excessive elevation or reduction of soluble uric acid (sUA) levels has been linked to some of pathological states, raising another subject that sUA at physiological levels may be essential for the maintenance of health. Yet, the fundamental physiological functions and molecular targets of sUA remain largely unknown. Using enzyme assays and in vitro and in vivo metabolic assays, we demonstrate that sUA directly inhibits the hydrolase and cyclase activities of CD38 via a reversible non-competitive mechanism, thereby limiting nicotinamide adenine dinucleotide (NAD+) degradation. CD38 inhibition is restricted to sUA in purine metabolism, and a structural comparison using methyl analogs of sUA such as caffeine metabolites shows that 1,3-dihydroimidazol-2-one is the main functional group. Moreover, sUA at physiological levels prevents crude lipopolysaccharide (cLPS)-induced systemic inflammation and monosodium urate (MSU) crystal-induced peritonitis in mice by interacting with CD38. Together, this study unveils an unexpected physiological role for sUA in controlling NAD+ availability and innate immunity through CD38 inhibition, providing a new perspective on sUA homeostasis and purine metabolism.

Effects of bariatric surgery on hyperuricemia and gout: a systematic review of the literature.

Gout is the most common form of inflammatory arthritis, and it is due to the deposition of monosodium urate crystals in the articular and extra-articular tissues. Body mass index is strongly correlated with elevated serum uric acid levels and gout is often associated with obesity and metabolic syndrome. Recommended nonpharmacological treatments for hyperuricemia and gout include dietary modifications and weight loss. Many studies have demonstrated that weight loss could reduce serum urate in patients with obesity and it is a commonly recommended treatment for gout. Bariatric surgery-induced weight loss exerts beneficial effects on hyperuricemia and gout, even if a possible raise of gout flares can be observed in patients with hyperuricemia early after surgery. The aim of this review is to systematically analyze all the studies published so far reporting a link between hyperuricemia and/or gout and bariatric surgery to obtain reliable figures on the incidence of this disease and describe the mechanisms underlying this association. Eleven studies accounting for 11,256 patients were included in the review. Mean preoperative prevalence of gout was 4.1%, while the preoperative prevalence of hyperuricemia ranged from 30.6% to 58%. After a mean follow-up of 8.5months, postoperative prevalence of gout significantly decreased to 2.9% (p < .007). The incidence of gout flares after bariatric surgery was higher in the early postoperative phase and progressively decreased over time. Similarly, serum uric acid concentrations showed an increase within the first postoperative month, which was followed by a progressive decrease below the preoperative value.

Material decomposition approaches for monosodium urate (MSU) quantification in gouty arthritis: a (bio)phantom study

BackgroundDual-energy computed tomography (DECT) is a noninvasive diagnostic tool for gouty arthritis. This study aimed to compare two postprocessing techniques for monosodium urate (MSU) detection: conventional two-material decomposition and material map-based decomposition.MethodsA raster phantom and an ex vivo biophantom, embedded with four different MSU concentrations, were scanned in two high-end CT scanners. Scanner 1 used the conventional postprocessing method while scanner 2 employed the material map approach. Volumetric analysis was performed to determine MSU detection, and image quality parameters, such as signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), were computed.ResultsThe material map-based method demonstrated superior MSU detection. Specifically, scanner 2 yielded total MSU volumes of 5.29 ± 0.28 mL and 4.52 ± 0.29 mL (mean ± standard deviation) in the raster and biophantom, respectively, versus 2.35 ± 0.23 mL and 1.15 ± 0.17 mL for scanner 1. Radiation dose correlated positively with detection for the conventional scanner, while there was no such correlation for the material map-based decomposition method in the biophantom. Despite its higher detection rate, material map-based decomposition was inferior in terms of SNR, CNR, and artifacts.ConclusionWhile material map-based decomposition resulted in superior MSU detection, it is limited by challenges such as increased artifacts. Our findings highlight the potential of this method for gout diagnosis while underscoring the need for further research to enhance its clinical reliability.Relevance statementAdvanced postprocessing such as material-map-based two-material decomposition might improve the sensitivity for gouty arthritis in clinical practice, thus, allowing for lower radiation doses or better sensitivity for gouty tophi.Key PointsDual-energy CT showed limited sensitivity for tophi with low MSU concentrations.Materiel-map-based decomposition increased sensitivity compared to conventional two-material decomposition.The advantages of material-map-based decomposition outweigh lower image quality and increased artifact load.Graphical

Development of gout in people with asymptomatic hyperuricemia: study protocol for a 5-year prospective cohort

IntroductionThe central biochemical cause of gout is hyperuricemia (elevated serum urate levels). Ultrasound features of monosodium urate (MSU) crystal deposition are common in people with asymptomatic hyperuricemia. However, it is...

Assessing Changes in Vascular Inflammation and Urate Deposition in the Vasculature of Gout Patients After Administration of Pegloticase Using Positron Emission Tomography and Dual-Energy Computed Tomography—A Pilot Study

We assessed changes in vascular inflammation and monosodium urate (MSU)-coded deposits after administration of Pegloticase in the vasculature of tophaceous gout patients using 18F-fluorodeoxyglucose (18F-FDG) Positron emission tomography/computed tomography (PET/CT) and dual-energy CT (DECT). Ten patients with tophaceous gout, intolerant or refractory to urate-lowering therapy (ULT), were treated with Pegloticase every two weeks for six months. 18F-FDG PET/CT and DECT were performed at baseline and after Pegloticase therapy to detect vessel wall inflammation (Standard uptake value, SUVmean, and SUVmax) and vascular MSU-coded deposition (MSU volume). Data were summarized using means and standard deviations. Baseline and follow-up values were compared for each variable using mixed-effect models. Significant decreases in SUVmean (p = 0.0003) and SUVmax (p = 0.009) were found with a trend towards a decrease in vessel wall MSU volume after treatment. There was a significant decrease in serum urate, correlating with reduction in SUVmean (R2 = 0.65), with a trend towards a decrease in CRP and blood pressure in all patients. Despite the small sample size, we were able to demonstrate a decrease in vessel wall inflammation and a trend towards a decrease in MSU volume by intensively lowering serum urate. These findings suggest that MSU-coded deposits and hyperuricemia may play a role in vascular wall inflammation. It remains to be seen whether this correlates with a decrease in adverse cardiovascular outcomes.

Physiopathological Aspects of Synovial Fluid and Membrane in Psoriatic Arthritis

Background: Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy characterized by a variety of clinical manifestations, mainly affecting joints and entheses, but also skin, nails, the eye, and the intestine. Objectives: In this review, we describe the essential characteristics of both synovial membranes and synovial fluid (SF) in PsA. Similarly to other inflammatory arthritis, the histological peculiarities in PsA synovitis are lining hyperplasia, neoangiogenesis, and sublining infiltration by immune cells and inflammatory mediators. Synovial effusions are frequent in PsA patients and SF analysis allows us to determine the pathological process occurring in the joint. Routine examinations help clinicians in defining the inflammatory status and possibly the detection of specific cell subsets. In addition, pathogenic crystals including monosodium urate and calcium pyrophosphate may be found in PsA SF. Conclusions: SF represents a potential substrate to identify the biomarkers that are useful to predict disease progression and response to medications in PsA patients, thus guiding the choice of appropriate and tailored pharmacological treatment.

Transcriptomic Analysis of THP-1 Cells Exposed by Monosodium Urate Reveals Key Genes Involved in Gout.

Gout is a common inflammatory arthritis, which is mainly caused by the deposition of monosodium urate (MSU) in tissues. Transcriptomics was used to explore the pathogenesis and treatment of gout in our work. The objective of the study was to analyze and validate potential therapeutic targets and biomarkers in THP-1 cells that were exposed to MSU. THP-1 cells were exposed to MSU. The inflammatory effect was characterized, and RNA-Seq analysis was then carried out. The differential genes obtained by RNA-Seq were analyzed with gene expression omnibus (GEO) series 160170 (GSE160170) gout-related clinical samples in the GEO database and gout-related genes in the GeneCards database. From the three analysis approaches, the genes with significant differences were verified by the differential genes' transcription levels. The interaction relationship of long non-coding RNA (lncRNA) was proposed by ceRNA network analysis. MSU significantly promoted the release of IL-1β and IL-18 in THP-1 cells, which aggravated their inflammatory effect. Through RNA-Seq, 698 differential genes were obtained, including 606 differential mRNA and 92 differential `LncRNA. Cross-analysis of the RNA-Seq differential genes, the GSE160170 differential genes, and the gout-related genes in GeneCards revealed a total of 17 genes coexisting in the tripartite data. Furthermore, seven differential genes-C-X-C motif chemokine ligand 8 (CXCL8), C-X-C motif chemokine ligand 2 (CXCL2), tumor necrosis factor (TNF), C-C motif chemokine ligand 3 (CCL3), suppressor of cytokine signaling 3 (SOCS3), oncostatin M (OSM), and MIR22 host gene (MIR22HG)-were verified as key genes that analyzed the weight of genes in pathways, the enrichment of inflammationrelated pathways, and protein-protein interaction (PPI) nodes combined with the expression of genes in RNA-Seq and GSE160170. It is suggested that MIR22HG may regulate OSM and SOCS3 through microRNA 4271 (miR-4271), OSM, and SOCS3m; CCL3 through microRNA 149-3p (miR-149-3p); and CXCL2 through microRNA 4652-3p (miR-4652-3p). The potential of CXCL8, CXCL2, TNF, CCL3, SOCS3, and OSM as gout biomarkers and MIR22HG as a therapeutic target for gout are proposed, which provide new insights into the mechanisms of gout biomarkers and therapeutic methods.

Epigenomic Reprogramming in Gout

Gout is a crystal-induced arthropathy in which monosodium urate (MSU) crystals precipitate within joints as a result of persistent hyperuricemia and elicit an inflammatory response. An intriguing aspect is the occurrence of gout in only 10–15% of hyperuricemic individuals, suggesting the presence of additional risk factors. Although MSU crystal deposition is widely recognized as the cause of gout flares, the variability in initiating the inflammatory response to hyperuricemia and MSU deposition is not well understood. Several studies bring up-to-date information about the environmental and genetic influences on the progression towards clinical gout. Elevated urate concentrations and exposure to different external factors precipitate gout flares, highlighting the potential involvement of epigenetic mechanisms in gouty inflammation. A better understanding of the alteration of the epigenetic landscape in gout may provide new perspectives on the dysregulated inflammatory response. In this review, we focus on understanding the current view of the role of epigenomic reprogramming in gout and the mechanistic pathways of action.

Imaging human coronary cholesterol/urate crystals with cross-polarized micro-optical coherence tomography.

Birefringent crystals such as monosodium-urate (MSU) and cholesterol crystals (CC) likely contribute to the progression of coronary artery disease (CAD) due to their potential to exacerbate inflammation through inflammatory cytokine activation. Here, we present cross-polarized micro-optical coherence tomography (CP-µOCT) for visualizing individual birefringent crystals in human coronary arteries. Human cadaver coronary arteries with a history of CAD with or without gout were dissected for CP-µOCT imaging. Specimens were processed for histological identification of birefringence under polarization light microscopy (PLM). CP-µOCT visualized needle-crystals that appeared as long projections in orthogonal planes, and PLM confirmed that CP-µOCT-delineated needle-crystals demonstrated negative birefringence. The needle-crystals were dissolved after immersion in uricase (p < 0.05), and thus were MSU. CP-µOCT was three-dimensionally volume-rendered for counting MSU and CCs in 79 regions of interest sized [750 (x) × 500 (y) × 400 (z) µm]. Crystal counts were normalized by the total coronary length utilized. The relationship between CP-µOCT-delineated MSU counts and those seen in corresponding histology, and the difference in coronary MSU amongst gout vs. non-gout patients was analyzed. CP-µOCT-delineated MSU counts were significantly correlated with MSU counted by PLM-based histology (R = 0.98, p < 0.01), and with histology-derived intimal thickening (R = 0.51, p < 0.01). MSU and CCs were both significantly greater in gout patients compared with non-gout patients (p < 0.05). These results demonstrate a significant increase in CP-µOCT-delineated crystals in gout vs. non-gout patients, suggesting that this technology can be used to improve our understanding of crystal-driven coronary pathogenesis.

Zinc oxide nanoparticles made with Phyla nodiflora leaf extract have anti-hyperuricemic effect on monosodium urate crystal-induced gouty arthritis

Zinc oxide nanoparticles made with Phyla nodiflora leaf extract have anti-hyperuricemic effect on monosodium urate crystal-induced gouty arthritis

Transcutaneous auricular vagus nerve stimulation mitigates gouty inflammation by reducing neutrophil infiltration in BALB/c mice

Gouty inflammation, caused by uric acid crystal deposition, primarily affects tissues around the toe joints and triggers potent inflammatory responses. Current treatments focus on alleviating inflammation and pain using pharmaceutical agents, which can lead to side effects and complications. This has generated interest in non-pharmacological interventions, such as non-invasive vagus nerve stimulation (VNS). In this study, we explored the anti-inflammatory mechanisms of transcutaneous auricular vagus nerve stimulation (taVNS) in a mouse model of acute gout. Gouty inflammation was induced by injecting monosodium urate (MSU) crystals into the ankle joints of BALB/c mice. The effects of taVNS on the expression of inflammatory cytokines and chemokines in the ankle joint tissue were assessed using real-time quantitative PCR (qPCR), western blotting, histological assessments (H&E staining), and immunohistochemistry (IHC). The role of α7 nicotinic acetylcholine receptors (α7nAChR) was also evaluated by signal blocking. Our findings revealed that MSU significantly elevated gout-associated inflammatory cascades and mediators in the ankle joint. Notably, taVNS at 200 µA and 25 Hz effectively reduced these inflammatory responses, decreasing neutrophil infiltration and chemoattraction within the tissue. taVNS showed significant anti-inflammatory properties by suppressing neutrophil activity, offering a novel therapeutic approach for gout beyond conventional pharmacological methods. Additionally, taVNS holds potential for managing various chronic joint diseases. These results highlight taVNS as a promising non-pharmacological therapy for chronic inflammation.

Understanding the interplay between psoriatic arthritis and gout: "Psout".

The interplay between Psoriatic arthritis and Gout is a current diagnostic challenge faced by many physicians and researchers. We aimed at reviewing the coexistence of gout and its features such as hyperuricemia and deposition of monosodium urate crystals in patients with psoriatic arthritis (PsA). We also focused on a brief presentation of the pathophysiology underneath the interplay between PsA and gout, and ultimately on recommendation of approaches for the differential diagnosis. The literature search for this narrative review was conducted using PubMed and Medline and after retrieving and screening the references, articles were selected according to the inclusion and exclusion criteria. Part of the assessed studies reported the coexistence of PsA and gout (Psout) and its association with several clinical outcomes among affected patients. Other studies stressed incidences of misdiagnosis of gout with PsA and vice versa. Additionally, the presence of hyperuricemia in PsA patients could interfere with the patient's characteristics and outcomes of their treatment. Further research on the assessment and clinical course of Psout is required to develop an official protocol for its diagnosis and treatment.

A Novel Polarized Light Microscope for the Examination of Birefringent Crystals in Synovial Fluid

Background: The gold standard for crystal arthritis diagnosis relies on the identification of either monosodium urate (MSU) or calcium pyrophosphate (CPP) crystals in synovial fluid. With the goal of enhanced crystal detection, we adapted a standard compensated polarized light microscope (CPLM) with a polarized digital camera and multi-focal depth imaging capabilities to create digital images from synovial fluid mounted on microscope slides. Using this single-shot computational polarized light microscopy (SCPLM) method, we compared rates of crystal detection and raters’ preference for image. Methods: Microscope slides from patients with either CPP, MSU, or no crystals in synovial fluid were acquired using CPLM and SCPLM methodologies. Detection rate, sensitivity, and specificity were evaluated by presenting expert crystal raters with (randomly sorted) CPLM and SCPLM digital images, from FOV above clinical samples. For each FOV and each method, each rater was asked to identify crystal suspects and their level of certainty for each crystal suspect and crystal type (MSU vs. CPP). Results: For the 283 crystal suspects evaluated, SCPLM resulted in higher crystal detection rates than did CPLM, for both CPP (51%. vs. 28%) and MSU (78% vs. 46%) crystals. Similarly, sensitivity was greater for SCPLM for CPP (0.63 vs. 0.35) and MSU (0.88 vs. 0.52) without giving up much specificity resulting in higher AUC. Conclusions: Subjective and objective measures of greater detection and higher certainty were observed for SCPLM over CPLM, particularly for CPP crystals. The digital data associated with these images can ultimately be incorporated into an automated crystal detection system that provides a quantitative report on crystal count, size, and morphology.

Phillyrin inhibits oxidative stress and neutrophil extracellular trap formation through the KEAP1/NRF2 pathway in gouty arthritis.

Gouty arthritis (GA) is an inflammatory disorder characterized by deposition of monosodium urate (MSU) crystal in joints. Phillyrin, a natural compound with anti-inflammatory properties, shows promise in mitigating inflammatory responses. This study investigates the therapeutic potential of phillyrin in GA and explores its mechanisms of action. GA was induced in mice via intraarticular MSU injection, and joint inflammation, inflammatory cell infiltration, and their level in serum/tissue were assessed. Key proteins in the NF-κB and NLRP3 pathways were examined using western blot analysis. The impact of phillyrin on oxidative stress, neutrophil extracellular trap (NET) formation, and neutrophil accumulation was evaluated by measuring CD11b + Ly6G + cells, MPO, CitH3, extracellular DNA ratio, and oxidative stress markers. In vitro studies assessed the effects of phillyrin on oxidative stress, cell viability, cytokine production, and NET formation in MSU-treated neutrophils. The KEAP1/NRF2 pathway's role was analyzed using ML385, an NRF2 inhibitor. Phillyrin significantly reversed MSU-induced ankle swelling and inflammatory cell infiltration in joint tissues. It suppressed pro-inflammatory cytokines and proteins in the NF-κB and NLRP3 pathways. Phillyrin reduced neutrophil infiltration, evidenced by lower MPO activity and NET formation, marked by reduced CitH3 expression. In vitro, phillyrin inhibited inflammatory marker expression and NET formation without affecting cell viability. It also restored antioxidant enzyme levels and reduced ROS production, regulating the KEAP1/NRF2 pathway, enhancing NRF2 expression and stability. These effects were reversed by NRF2 inhibition with ML385. Phillyrin alleviates GA by reducing joint inflammation, inhibiting NET formation, and suppressing oxidative stress through NRF2 modulation.

Real-Time, High-Throughput Microscopic Quantification of Human Neutrophil Extracellular Trap Release and Assessing the Pharmacology of Antagonists.

Neutrophils play an important role in innate immune defense by using several strategies, including the release of neutrophil extracellular traps (NETs) in a process referred to as NETosis. However, in the past two decades, it has become clear that the accumulation of NETs in tissues contributes to the pathophysiology of multiple inflammatory and autoimmune diseases. Therefore, interest in the development of NETosis antagonists has risen. Variable and non-standardized methods to detect and analyze NETosis were developed concomitantly, each with its own advantages and limitations. Here, we describe a real-time microscopy method for the quantification of human NET release, allowing to study NETosis as well as NET inhibition in a high-throughput manner. The surface area-based semi-automated analysis recognizes NETs and distinguishes them from non-netting activated neutrophils. We demonstrate that the non-physiological NETosis inducers, calcium ionophore and phorbol-12-myristate-13-acetate (PMA), trigger the release of NETs with different characteristics and kinetics. Furthermore, we show that this approach allows studying NET release in response to disease-relevant stimuli, including immune complexes, N-Formylmethionine-leucyl-phenylalanine (fMLF), monosodium urate crystals, and calcium pyrophosphate crystals. To exemplify the utility of this method to study NETosis antagonists, we used CIT-013, a first-in-class monoclonal antibody inhibitor of NET release. CIT-013 targets citrullinated histone H2A and H4 and efficiently inhibits NET release with an IC50 of 4.6 nM. Other anti-histone antibodies tested lacked this NETosis-inhibitory capacity. Altogether, we demonstrate that this protocol enables specific, reliable, and reproducible high-throughput quantification of NETs, enhancing the study of NET release characteristics, kinetics, and pharmacology of NETosis antagonists.

Therapeutic Potential of Methanolic Stem Extract of Costus afer on Serum Uric Acid, Tumor Necrosis Factor-alpha (TNF-α), and Interleukin-6 (IL-6) Levels in Monosodium Urate (MSU)-Induced Gouty Arthritis in Wistar Rats

The therapeutic potential of methanolic stem extracts of Costus afer was investigated to evaluate their effects on serum uric acid, TNF-α, and IL-6 levels, which are the key biomarkers associated with inflammatory and metabolic disorders like gouty arthritis. Qualitative and quantitative phytochemical analysis of C. afer indicated the presence of flavonoids, alkaloids, phenol, anthraquinone and glycosides, these bioactive compounds have been implicated for numerous medicinal uses and as such the therapeutic potentials of the extract were investigated by administering varying doses (100 mg/kg, 200 mg/kg, and 400 mg/kg) of the extract to a Wistar rat model with induced gouty arthritis and assessing its impact compared to a control group and an untreated MSU group. The results revealed that the extracts significantly reduced ( serum uric acid levels in a dose-dependent manner, with the high dose achieving a reduction below the control level. Additionally, the extracts effectively decreased ( TNF-α and IL-6 levels, indicating potent anti-inflammatory properties. The high dose exhibited the most substantial reduction in these biomarkers, underscoring the extract’s therapeutic potential. These findings support the traditional use of C. afer and provide scientific validation for its application in managing hyperuricemia and inflammatory conditions.

A genome-wide association analysis reveals new pathogenic pathways in gout.

Gout is a chronic disease that is caused by an innate immune response to deposited monosodium urate crystals in the setting of hyperuricemia. Here, we provide insights into the molecular mechanism of the poorly understood inflammatory component of gout from a genome-wide association study (GWAS) of 2.6 million people, including 120,295 people with prevalent gout. We detected 377 loci and 410 genetically independent signals (149 previously unreported loci in urate and gout). An additional 65 loci with signals in urate (from a GWAS of 630,117 individuals) but not gout were identified. A prioritization scheme identified candidate genes in the inflammatory process of gout, including genes involved in epigenetic remodeling, cell osmolarity and regulation of NOD-like receptor protein 3 (NLRP3) inflammasome activity. Mendelian randomization analysis provided evidence for a causal role of clonal hematopoiesis of indeterminate potential in gout. Our study identifies candidate genes and molecular processes in the inflammatory pathogenesis of gout suitable for follow-up studies.

Advances in Gouty Arthritis Management: Integration of Established Therapies, Emerging Treatments, and Lifestyle Interventions.

Gouty arthritis, a prevalent inflammatory condition characterized by the deposition of monosodium urate crystals within joints, often results in debilitating pain and inflammation. Conventional therapeutic approaches, including nonsteroidal anti-inflammatory drugs, corticosteroids, and urate-lowering agents such as allopurinol and febuxostat, often have limitations such as adverse effects, drug interactions, and suboptimal patient compliance. This review presents a comprehensive overview of both established and emerging therapeutic strategies, developed between 2019 and 2024, for gouty arthritis; the review focuses on their mechanisms of action, efficacy, and safety profiles. Novel therapeutic approaches include pharmaceutical plant additives (e.g., Citrullus colocynthis, Atractylodes lancea), anti-inflammatory agents such as canakinumab and ozone therapy, and complementary therapies such as warm ginger compresses, Qingpeng ointment, and various lifestyle modifications. These strategies offer promising alternatives to conventional treatments by targeting uric acid metabolism, inflammatory pathways, and crystal formation, potentially reducing reliance on standard medications and minimizing adverse effects. Although therapies such as canakinumab have demonstrated significant efficacy in reducing gout flares, others such as polyphenol-rich foods offer favorable safety profiles. Further research, including large-scale clinical trials, is warranted to validate these findings and integrate these strategies into clinical practice to improve patient outcomes and quality of life.

Downregulation of type I interferon signalling pathway by urate in primary human PBMCs.

Type I interferons (IFN1s) mediate innate responses to microbial stimuli and regulate interleukin (IL)-1 and IL-1 receptor antagonist (Ra) production in human cells. This study explores interferon-stimulated gene (ISG) alterations in the transcriptome of patients with gout and stimulated human primary cells in vitro in relation to serum urate concentrations. Peripheral blood mononuclear cells (PBMCs) and monocytes of patients with gout were primed in vitro with soluble urate, followed by lipopolysaccharide (LPS) stimulation. Separately, PBMCs were stimulated with various toll-like receptor (TLR) ligands. RNA sequencing and IL-1Ra cytokine measurement were performed. STAT1 phosphorylation was assessed in urate-treated monocytes. Cytokine responses to IFN-β were evaluated in PBMCs cultured with or without urate and restimulated with LPS and monosodium urate (MSU) crystals. Transcriptomics revealed suppressed IFN-related signalling pathways in urate-exposed PBMCs or monocytes which was supported by diminishment of phosphorylated STAT1. The stimulation of PBMCs with IFN-β did not modify the urate-induced inflammation. Interestingly, in vivo, serum urate concentrations were inversely correlated to in vitro ISG expression upon stimulations with TLR ligands. These findings support a deficient IFN1 signalling in the presence of elevated serum urate concentrations, which could translate to increased susceptibility to infections.