Transcriptomic Profiling of Monosodium Urate-induced Inflammation in a Mouse Model of Acute Gout

Abstract

Gout is the most common inflammatory arthritis, caused by the deposition of monosodium urate (MSU) crystals in joints, leading to acute flares characterized by intense pain and inflammation. This study aimed to investigate the molecular mechanisms underlying MSU-induced inflammation in gout by reanalyzing RNA-seq data from an acute mouse model. RNA was isolated from MSU-injected and control mouse ankle joints, and transcriptomic analysis was performed using RNA-seq analysis. Differential gene expression analysis identified significantly up-regulated genes, such as Ptx3, Il1b, Nlrp3, Hdc, Ccl7, and Toll-like receptors, many of which are key inflammatory cytokines, chemokines, and their receptors as well as mediators involved in histamine biosynthesis. Among the significantly down-regulated genes, such as Col8a2, Lgals12, and Adam33, some are associated with structural and metabolic pathways. Additionally, gene ontology and pathway enrichment analyses provided insights into biological processes and molecular pathways affected by MSU-induced inflammation. Importantly, the analysis also revealed that MSU-induced inflammation disrupts tissue repair mechanisms, as shown by the downregulation of wound healing and extracellular matrix organization genes, including Vegfb, Fgf1, Vwf, Fzd7, Plat, Clec10a, CD151, F3, and Alox5. Functional enrichment analysis further confirmed suppression of biological processes related to tissue remodeling and activation of innate immune responses. These results suggest that in addition to promoting acute inflammation, MSU crystals inhibit resolution and repair pathways, thereby potentially contributing to chronic joint damage in gout. These findings offer further insights into the pathophysiology of gout and hold the potential to inform future therapeutic strategies aimed at both suppressing inflammation and promoting tissue repair.

Keywords RNA-seq, inflammasome, chemokine, cytokine, Toll-like receptors, innate immune cells, extracellular matrix, wound healing, pathway

Introduction

Gout is the most common and debilitating form of inflammatory arthritis in adults¹. It is characterized as self-resolving acute flares that typically last 7-10 days, with intense pain, swelling, and erythema in affected joints². In 2020, approximately 55.8 million cases of gout were reported globally, representing a 22.5% increase since 1990. The condition disproportionately affects males, with a prevalence 3.26 times higher than in females, and its incidence increases with age. The total number of gout cases is projected to reach 95.8 million by 2050, driven primarily by population growth³. 

Gout is caused by the buildup of monosodium urate (MSU) crystals in or around these joints⁴. Urate is a natural product of purine degradation. Excessive purine breakdown increases the blood urate level. This condition is known as hyperuricemia⁴, defined as an elevated serum uric acid level exceeding the solubility threshold of 6.8 mg/dL in women and 7 mg/dL in men⁵. High levels of urate result in the deposition of MSU crystals in the body, most commonly in the kidney, joints, and periarticular tissues. These sharp MSU crystals in the joints cause acute pain and inflammation during gout flares. 

While most individuals with hyperuricemia remain asymptomatic, approximately 10% develop gout, often precipitated by dietary and lifestyle factors, comorbid conditions, or genetic predispositions. Foods rich in purines, such as red meat, organ meat, and seafood, as well as alcohol consumption, are strongly associated with gout. Comorbid conditions, including obesity, diabetes, hypertension, and chronic kidney disease, further elevate the risk of developing hyperuricemia and gout⁴. 

The hallmark of gout is acute inflammation driven by activation of the innate immune system⁶. MSU crystals formed in the joints trigger the acute inflammatory responses following the activation of innate immune cells such as macrophages, mast cells, and neutrophils, and the formation of inflammasomes. This process leads to increased productions of IL-1 family cytokines such as IL-1β, a key proinflammatory cytokine in the pathogenesis of gout flares⁷. The activation of chemokine and cytokine networks promotes the recruitment of additional immune cells to the site of crystal deposition, amplifying the inflammatory response and resulting in the clinical manifestations of gout flares⁴. Despite the acute nature of gout flares, the disease has chronic implications, as repeated flares can lead to joint deformity, tophus formation, and chronic arthritis⁸. Current therapies such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and urate-lowering therapies (ULTs) are effective in managing symptoms and reducing urate levels. Nonetheless, further understanding of the mechanism underlying gout will identify key molecular pathways involved and lead to more effective targeted treatment of gout as well as management of complications, such as chronic kidney disease and cardiovascular conditions, caused by gout. Moreover, understanding genetic and biochemical factors can help advance early detection and prevention strategies of gout.

To this end, animal models of gout have been developed to study the molecular and cellular pathways⁹. Formation of MSU crystals is the first critical step in the progression of gout. MSU crystals trigger inflammatory cellular responses¹⁰. Gout in mouse ankle joint induced by MSU crystals is used to investigate the mechanism of MSU-triggered inflammation¹¹. This study utilized an RNA-seq dataset from an acute gout model in mice¹ to investigate the transcriptomic changes in MSU-injected ankle joints compared to control joints. The transcriptomic changes found in MSU-induced gouty ankle joints, including upregulation of key inflammatory mediators, activation of innate immune pathways, and suppression of structural and repair-related genes, provide insights into the molecular drivers of gouty inflammation and offer potential targets for therapeutic intervention.

Methods and Materials

MSU-induced Mouse Gout Model

The RNA-seq dataset GSE190138 was downloaded from NCBI website (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE190138) and reanalyzed. Briefly, this dataset was generated from the ankle joints of a C57BL/6 murine gout model, which were treated with intra-articular injection of MSU or PBS as a control¹. Sterile MSU crystals were prepared and suspended in phosphate-buffered saline (PBS, 1x) at a concentration of 20 mg/mL. In this model, the right ankle joint of mice in the MSU group received an intra-articular injection of 100 μL MSU suspension (2 mg MSU crystals in total). For the control group, 100 μL PBS solution was injected into the right ankle joint. Eight hours after injections, the degree of joint swelling was measured with an electronic vernier caliper and photographed. Mechanical hyperalgesia was evaluated using Von Frey filament tests.

RNA-seq library preparation

Eight hours post-injections of MSU crystals or 1 x PBS, mice were anesthetized with isoflurane and decapitated. Ankle joints, DRG, and spinal cord were collected and stored in RNAlater (Thermo Fisher Scientific). Total RNAs were extracted using TRIzol reagent (Thermo Fisher Scientific). RNAseq libraries were prepared for sequencing using a VAHTS Universal V6 RNAseq Library Prep Kit (Vazyme) for Illumina. The library was sequenced on an Illumina HiSeq platform. 

RNA-seq data quantification

Raw sequencing reads were filtered to remove Low-quality reads. The reads were transformed to Log2 counts and quantified using featureCounts¹² to assign reads to annotated genes based on the Ensemble gene annotations. The resulting count matrix was used for downstream analyses¹³.

Differential expression genes (DEGs)

RNA was sequenced on an Illumina HiSeq platform. Differential expression genes (DEGs) analysis was performed with the DESeq2 1.40.2/20 version of R package¹⁴. Genes were considered differentially expressed with Log (fold change) |log2FC| >0.25 and false discovery rate (FDR) < 0.05, calculated by using FDR = FP/(TP+FP) where TP were the true positives and FP were the false positives. Functional enrichment analysis was conducted using the clusterProfiler package¹⁵.

Gene Ontology and Pathway Enrichment Analysis

Significantly upregulated and downregulated genes were subjected to Gene Ontology (GO) and KEGG pathway enrichment analysis using the clusterProfiler package in R¹⁵. Enrichment results with FDR < 0.05 were considered significant, suggesting biological processes, cellular components and molecular function pathways involved in the observed transcriptional changes.

Visualization and data interpretation 

Unsupervised Principal Component Analysis (PCA) was used to visualize any distinct groups of samples by projecting high-dimensional data onto a lower-dimensional space. It is typically represented as a scatter plot where each point represents a sample colored based on its group, allowing for easy visual identification of distinct clusters between groups¹⁶. Volcano plots, heatmaps, and gene pathway networks were generated by using ggplot2, heatmap, and enrichment plot packages in R¹⁷. These visualizations were used to summarize differential expression results and identify key genes and pathways involved in the study.

Results

Distinct gene expression profiles of MSU-injected ankle joints

Unsupervised PCA was performed to assess transcriptional variation between MSU-treated and control ankle joints. The PCA scatterplot demonstrated distinct clustering of MSU-treated samples separate from controls, reflecting the significant transcriptional differences induced by MSU crystal injections. These results indicate that MSU treatment led to significant changes in gene expression in gouty ankles compared to healthy controls (Fig.1).

Up – and downregulated genes in MSU-treated ankle joints 

Analysis of the RNA-seq data identified a total of 5,505 DEGs in the MSU-treated ankle joints compared to controls. Of these DEGs, 2,599 were upregulated and 2,906 were downregulated. The remaining 8712 genes did not show any significant changes between the two groups.

The top 20 up-regulated DEGs were Ptx3, Lif, Mmp3, Adamts4, Timp1, Tnfsf11, Clec4e, Tnfaip3, Slc7a11, Slfn4, Clec4d, Il1b, Cd14, Nlrp3, Ptgs2, Oas3, Hdc, Isg15, Lcn2, and Krt6b (Fig.2A). Notably, this list included the inflammatory cytokine Il1b, and inflammatory mediator Hdc involved in histamine biosynthesis. The top 20 down-regulated DEGs were Col8a2, Gdf10, Lgals12, Adam33, Gucy1a1, Mycl, Mrgprf, Col4a6, Nnat, Dact3, Mt4, Selenbp1, Ogn, Clec3a, Alox12e, Plin1, Clic5, Vsig8, Krtap28-10, and Krtap1-4 (Fig.2A&B). 

A volcano plot further visualized the up- and downregulated genes in MSU-induced gouty mouse ankle joints (Fig. 3A). A pie chart graph illustrated the percentages of up- and downregulated genes among all genes expressed by the cells of ankle joints (Fig. 3B).

Upregulated chemokines and receptors in MSU-injected ankle joints 

Chemokine and their receptors play important roles to chemotaxis immune cells to the inflammation site. In gouty ankles, upregulations of chemokines Ccl2, Ccl6, Ccl7, Ccl9, Ccl11, Ccl22, Cxcl13, Cxcl14, and Cxcl16 (Fig. 4A) and chemokine receptors Ccr1, Ccr2, Ccr5, Cxcr2 and Cxcr4 were observed (Fig. 4B). CCL7, for example, mainly acts as a chemoattractant for several leukocytes, including monocytes, eosinophils, basophils, dendritic cells (DCs), neutrophils, NK cells and activated T lymphocytes. In the gouty ankles, these chemokines likely facilitate the recruitment of immune cells, such as monocytes, macrophages, and neutrophils, to sites of inflammation. The pronounced upregulation of these cytokines and their receptors suggests their pivotal role in driving acute inflammation in response to MSU crystals.

Up-regulation of IL1 cytokines and receptors in MSU-injected ankle joints 

Cytokines from the IL1 family including Il1a, Il1b, Il33 and Il36g, and their receptors Il1r1, Il1r2, Il1rap, Il1rl1, Il18r1, and Il18rap plus the intracellular signal molecules Myd88, Irak2 and Irak4 were up-regulated in the MSU-injected ankle joints compared with the controls (Fig. 5A&B). Il1⍺ and Il1β bind with their receptors Il1r1/Il1rap, and IL33 binds with its receptor Il1rl1/Il1rap. Additionally, intracellular molecules Myd88, Irak2, Irak4, which are downstream in the signaling pathway upon binding of IL1 family members with their receptors, were upregulated in the MSU-induced gouty joints (Fig. 5C). 

Up-regulation of Toll-like receptors (TLRs) in the MSU-injected ankle joints 

In the MSU-injected ankle joints, there were upregulations of Tlr1, Tlr2, Tlr3, Tlr4, Tlr6, Tlr7, Tlr8, and Tlr13 compared with the controls (Fig.6). TLRs are a group of single spanning receptors in the innate immune system. As pattern recognition receptors, TLRs play important roles in detecting MSU crystals and initiating downstream inflammatory signaling cascades. Their upregulations likely result in increased production of proinflammatory cytokines, particularly IL1β, aggravating the inflammation in the gouty ankle joints. 

Downregulation of extracellular matrix organization and wound healing in the MSU-injected ankle joints 

Analysis of the RNA-seq data identified a total of 2,906 downregulated DEGs in the MSU-treated ankle joints compared to controls. Within these 2906 DEGs, MSU-treated ankle joints had lower expression levels of extracellular matrix genes such as collagen and laminin (Fig. 7A) and wound healing marker genes such as Vegfb, Fgf1, Vwf, Fzd7, Plat, Clec10a, CD151, F3, and Alox5 (Fig. 7B). These results indicated the impair wound healing in the MSU-treated ankle joint.

Enriched pathways in MSU-induced gouty ankle joints

GO functional enrichment analysis of up- and downregulated DEGs from the ankles indicated most affected pathways involved in biological processes, cellular components, and molecular functions in the MSU-induced gouty mice. The most enriched biological processes included ribonucleoprotein complex biogenesis, ribosome biogenesis, rRNA metabolic process, regulation of innate immune response and activation of innate immune response, while downregulated genes are significantly associated with cell-cell signaling by WNT, lipid catabolic process, and extracellular matrix organization (Fig.8A). In the cell component enrichment analysis, the most up-regulated pathways were preribosome, ribonucleoprotein granule, endocytic vesicle, and phagocytic vesicle, and the most downregulated pathways were collagen-containing extracellular matrix, myofibril, and cytoskeleton (Fig. 8B). In molecular function pathway analysis, the most up-regulated pathways were ribonucleoprotein complex binding, immune receptor activity, and cytokine receptor activity, while the most downregulated pathways were GTPase regulator activity, actin binding, and phospholipid binding (Fig. 8C).

Discussion

In this study, the comprehensive transcriptomic analysis of MSU-induced acute inflammation in mouse ankle joints offers unique insights into the molecular mechanisms driving gout flares. Of note, the upregulations of chemokine and chemokine receptors, IL1 family cytokines and cytokine receptors, Toll-like receptors, all likely contribute to the acute inflammations in gouty ankle joints. Additionally, MSU also significantly impaired pathways associated with wound healing and extracellular matrix organization.

The upregulation of IL-1 family cytokines, including Il1b, Il33, and Il36g, and their corresponding receptors, suggest key involvements of these molecules in the inflammatory cascade. IL-1β, in particular, is a critical mediator of gout flares, which amplifies immune responses, and recruits neutrophils to the inflamed joint¹⁸. The substantial increase in chemokine expression, such as Ccl2¹⁹ and Ccl7²⁰, further emphasizes the importance of chemotaxis in directing immune cells to sites of MSU crystal deposition. These findings are consistent with the characteristic acute inflammation and pain observed during gout flares. TLRs also emerged as significant contributors, with their upregulation indicating an enhanced ability to recognize MSU crystals and trigger inflammatory responses. TLR activation leads to downstream signaling pathways that culminate in the production of pro-inflammatory cytokines, thereby exacerbating the acute inflammatory state²¹. While inflammation is necessary for the resolution of MSU crystals, the downregulation of genes associated with extracellular matrix organization, such as Col8a2, suggests that acute gouty flares disrupt tissue homeostasis and repair. These disruptions may contribute to the joint damage and chronic arthritis often seen in patients with recurrent gout flares.

These results are consistent with previous reports that demonstrated the central role of IL-1β in mediating gout flares. For example, MSU crystals was shown to activate the NLRP3 inflammasome, leading to IL-1β secretion and intense joint inflammation in murine models²². Similarly, a review of clinical studies concluded that IL-1β is not only elevated in gout flares but also correlates with symptom severity²⁰. The upregulation of Il1b, Il1a, Il33, and their receptors observed in the present study is consistent with these findings and supports their mechanistic importance in acute inflammation. 

 Pathway enrichment analyses revealed that the upregulated pathways predominantly involve immune activation and cellular metabolism, suggesting robust inflammatory and metabolic activities in gouty joints. Conversely, the suppression of lipid catabolism and structural pathways indicates a shift in cellular priorities toward addressing inflammation, often at the expense of tissue integrity.

The above findings suggest potential targets for therapeutic intervention beyond current urate-lowering or anti-inflammatory drugs. IL-1 inhibitors such as anakinra and canakinumab, which block IL-1 signaling, have already shown promise in treating gout flares. The results herein support their continued development and clinical use. Likewise, modulating chemokine or TLR pathways may help dampen excessive immune cell infiltration and downstream cytokine release, suggesting a multi-pronged approach to managing both acute and chronic gout.

Moreover, the suppression of structural and metabolic pathways, including Col8a2 and other extracellular matrix genes, suggests that acute inflammation may come at the cost of joint integrity and repair mechanisms. Over time, this imbalance could predispose to tophus formation and joint deformity. This supports the need for early intervention strategies that not only reduce inflammation but also promote tissue remodeling and repair.

Beyond inflammation and pro-inflammatory cytokine and chemokine responses, MSU was also found to significantly impair pathways associated with wound healing and extracellular matrix organization. As shown in Figure 7, several genes involved in tissue repair processes, including Vegfb, Fgf1, Vwf, Fzd7, Plat, Clec10a, CD151, F3, and Alox5, were downregulated in MSU-injected ankle joints compared to controls. These genes play critical roles in angiogenesis, fibroblast proliferation, hemostasis, and epithelial regeneration, all of which are essential for effective wound healing²,²³,²⁴,²⁵,²⁶,²⁷,²⁸. For instance, the suppression of Vegfb and Fgf1, both key regulators of vascular and fibroblast responses, suggested compromised tissue perfusion and reduced regenerative capacity in inflamed joints. Similarly, reduced expression of Vwf and Plat, which are genes important for coagulation and fibrinolysis, indicated impaired vascular integrity and delayed resolution of tissue injury. These findings are consistent with previous reports in which persistent inflammation in gout were found to delay tissue remodeling and exacerbate joint damage². Moreover, Alox5, a gene involved in the biosynthesis of pro-resolving lipid mediators such as lipoxins, was also downregulated, further suggesting that the resolution phase of inflammation and tissue repair is actively suppressed during acute MSU-driven flares. Similarly, previous studies showed that MSU crystals not only trigger acute inflammation but also inhibit the processes necessary for healing, thereby contributing to chronic joint deterioration²⁹,³⁰. Overall, these results demonstrate that MSU-induced inflammation disrupts not only immune balance but also structural and repair mechanisms in affected tissues. Therapeutic approaches that promote resolution of inflammation and support tissue repair, such as pro-resolving lipid mediators or regenerative therapies, may therefore offer complementary benefits alongside anti-inflammatory agents in the management of gout.

This study has some limitations to consider. First, the dataset is limited by a small sample size (n = 3 per group), which may introduce variability and limit generalizability. Larger sample sizes are needed to confirm key transcriptional changes. Second, the use of an acute MSU-injection model may not fully replicate the complex chronic features of gout in humans, such as recurrent flares and crystal persistence. While the analysis herein focused on local joint tissues, systemic effects in organs such as the kidney and cardiovascular system were not explored. Future work should integrate transcriptomic profiles from systemic sites and chronic models to better understand whole-body impacts of gout. Additionally, a comparative cross-species analysis with existing human gout transcriptomic datasets could provide valuable translational insight, where the variability in patient populations, disease stages, and tissue types in available human datasets should be taken into consideration. Lastly, although IL-1 inhibitors, such as anakinra, have shown clinical efficacy in gout management, this study does not experimentally evaluate these treatments. Therefore, any therapeutic implications based on transcriptomic data must be interpreted cautiously. Further research is needed to validate these targets and assess their potential in preclinical or clinical settings.

Conclusion

RNA-seq analysis of MSU-induced gouty mouse ankle joints revealed distinct transcriptomic signatures marked by elevated inflammatory and innate immune responses and suppression of tissue structural pathways, as well as suppression of tissue structural and repair pathways. These results indicated a central role of IL-1 signaling, chemokine-mediated immune cell recruitment, and TLR activation in driving acute inflammation. Notably, the downregulation of key genes involved in angiogenesis, fibroblast proliferation, wound healing, and lipid mediator biosynthesis suggests that MSU not only triggers inflammation but also actively impairs tissue resolution and regeneration. Therapeutic strategies that inhibit IL-1β or target chemokine and TLR pathways may be effective in controlling acute flares. The downregulation of repair-associated genes also suggests potential avenues for mitigating chronic damage through tissue-supportive therapies. Future research should explore the efficacy of pathway-specific inhibitors in chronic models and investigate transcriptomic changes in systemic tissues to inform comprehensive gout treatment strategies. 

Acknowledgments

I would like to thank Dr. Qian Wang for her great support and guidance throughout this study.

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