Lymphatic vessels drain monosodium urate and activate immunity in gouty arthritis
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PROVIDER: PRJNA822357 | ENA |
REPOSITORIES: ENA
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Project description:Gouty Arthritis (GA) is caused by urate deposition in the joint capsule, cartilage, bone, and surrounding tissues to trigger recurrent attacks of acute joint inflammation. However, the clearance mechanism of urate deposition is still not clear. We aimed to investigate whether lymphatics vessels can drain monosodium and involve in the immune process of GA. Methods: Inguinal lymph nodes (LNs) in 4 normal volunteers and 4 patients with acute flare of GA were examined by ultrasound. Acute and chronic GA flare mouse models were established by intra-footpad administrations of monosodium urate (MSU) for 1 week or 1 month. Mice were treated with VEGFR-3 inhibitor or undergone popliteal lymph node (PLN) excision or PLN macrophage depletion. The severity of foot inflammation, lymphatic draining function, concentration of uric acid (UA), and macrophage population were examined. Macrophages were co-cultured with MSU-treated lymphatic endothelial cells (LECs) and differential gene expression of LECs was assessed by Agilent gene expression microarray. Results: 1) Draining LNs were enlarged in patients with GA flare and GA mouse models. 2) The lymphatic function and structure were abnormal in GA mouse models. 3) Acute GA mice had elevated UA levels in draining LNs, but not in the serum, while chronic GA mice had elevated UA levels in both LNs and serum. 4) Blockade of VEGFR-3 reduced foot inflammation in chronic GA mice. 5) MSU induces pro-inflammatory polarization of macrophages by inducing LEC inflammation. 6) PLN local depletion of macrophages or removal of PLNs alleviated foot inflammation in GA. Conclusions: Lymphatics drain MSU to the draining LNs to clear deposited urate in the distal extremity and induce LECs to stimulate macrophage pro-inflammatory response during GA. We have identified a novel mechanism about MSU clearance and pro-inflammatory macrophage activation, and provided possible therapeutic approach for GA.
2022-04-02 | GSE199950 | GEO
Project description:Gouty arthritis (GA) is a chronic and progressive disease that often develops due to high urate levels, leading to joint damage and characterized by an inflammatory immune microenvironment (IIMe). Quantitative proteomics further revealed D-N camouflaged with hybid membranes of M2 exosome and its parent microphage (D-N[EM2]) treated GA disease mechanisms.
2024-07-02 | PXD051823 | Pride
Project description:Aim of the study was to characterize at a molecular level (changes in transcriptomes) the effect of monosodium urate crystal (MSU) on HaCaT keratinocyte cell line. This was adressed by using a culture model. The HaCaT cell line (human keratinocytes) was stimulated by MSU (1mg/mL) vs control for 12 hrs. By using genome-wide expression profiling, we identified deregulation of functionally relevant gene networks.
2015-10-29 | GSE65931 | GEO
Project description:We used I-BET 151, an isoxazoloquinoline that specifically inhibits interaction of BET proteins with acetylated histones to restrict inflammatory tissue priming in a mouse model of iterated monosodium urate (MSU) crystal-induced arthritis. Systemic administration of I-BET 151 abolished the enhancement of arthritis upon repeated injection of MSU crystals.
2022-02-17 | GSE196679 | GEO
Project description:Aim of the study was to characterize at a molecular level (changes in transcriptomes) the effect of monosodium urate crystal (MSU) on HaCaT keratinocyte cell line. This was adressed by using a culture model. The HaCaT cell line (human keratinocytes) was stimulated by MSU (1mg/mL) vs control for 12 hrs. By using genome-wide expression profiling, we identified deregulation of functionally relevant gene networks. HaCaT were obtained from Cell Lines Service (Eppelheim, Germany) and grown in DMEM medium (PAN biotech, Aidenbach, Germany) supplemented with 10% FBS (Life Technology, Grand Island, NY, USA), L-glutamine and non-essential amino acid. Before the treatment HaCaT cells were cultured in serum-free medium for 12hrs. HaCaT were treated with MSU (1mg/ml) vs DMEM control for 12hrs then submitted to RNA extration and gene expression profiling. Triplicate experiments were performed: HaCaT control (n=3), MSU-treated (n=3).
2015-10-29 | E-GEOD-65931 | biostudies-arrayexpress
Project description:Objective. To identify novel monosodium urate (MSU) crystal-induced mRNAs by transcript profiling of isolated murine air pouch membranes. Methods. Nine hours after injecting crystals into air pouches, membranes were meticulously dissected away from the adjacent soft tissues. mRNA expression differences between inflamed and control membranes were determined by oligonucleotide microarray analysis. Induction of selected mRNAs was validated by real-time relative quantitative reverse transcriptase PCR (qPCR) in pouch membranes and murine peritoneal macrophages. Results. Eleven of the 12 most highly upregulated mRNAs related to innate immunity and inflammation. They included mRNAs encoding histidine decarboxylase (the enzyme that synthesizes histamine), interleukin (IL)-6, the cell surface receptors PUMA-g and TREM-1, and the polypeptides Irg1 and PROK-2. MSU crystals induced dramatic rises in these mRNAs in the pouch membrane within 3-8 hours after the surge in pro-inflammatory cytokine (IL-6, IL-1beta and TNFalpha) and immediate early gene (Egr-1) transcription, which occurred 1h after crystal injection. MSU crystals induced these mRNAs in cultured macrophages with similar kinetics but lower fold changes. In keeping with their downregulation by MSU crystals according to the microarrays, qPCR confirmed that TREM-2 and granzyme D mRNAs decreased 79% and 94%, respectively, in MSU crystal inflamed membranes. Conclusions. This analysis disclosed several genes previously not implicated in MSU crystal inflammation. Their rise after the early surge in cytokine mRNAs suggests that they may, for instance, amplify or perpetuate inflammation. Transcript profiling of the isolated air pouch membrane promises to be a powerful tool to identify genes acting at different stages of inflammation.
2008-05-23 | GSE11498 | GEO
Project description:Transcriptomic data on the response of macropohages to monosodium urate crystals (MSUc)
| PRJNA789541 | ENA
Project description:Objectives: In gout, flares of severely painful inflammatory arthritis intersect with metabolism, circadian rhythm, and macrophage activation. NAD+ is a necessary cofactor and key metabolite in cellular bioenergy homeostasis, and NAD+ suppresses the NLRP3 inflammasome and inflammation. However, cellular NAD+ declines in inflammatory states, associated with increased activity of the leukocyte-expressed NADase CD38. Gouty arthritis is principally prevented and treated with nonselective and frequently toxic drugs (colchicine, NSAIDs, corticosteroids). Hence, we tested the potential role of therapeutically targeting CD38 and NAD+ in gout. Methods: We studied cultured mouse wild type and CD38 knockout (KO) murine bone marrow derived macrophages (BMDMs) stimulated by monosodium urate (MSU) crystals, and the air pouch gout synovitis model. Results: MSU crystals induced CD38 in BMDMs in vitro, associated with NAD+ depletion, and IL-1b and CXCL1 release, effects reversed by pharmacologic CD38 inhibitors (apigenin, 78c). Mouse air pouch inflammatory responses to MSU crystals were blunted by CD38 KO and apigenin. Pharmacologic CD38 inhibition suppressed MSU crystal-induced NLRP3 inflammasome activation and increased anti-inflammatory SIRT3-SOD2 in macrophages. BMDM RNA-seq analysis of 176 differentially expressed genes (DEGs) revealed CD38 control of multiple MSU crystal-modulated inflammation pathways. The top DEGs included the circadian rhythm modulator GRP176, and the metalloreductase STEAP4 that mediates iron homeostasis, and promotes oxidative stress and NF-kB activation when it is overexpressed. Conclusion: CD38 and NAD+ depletion are druggable targets controlling the MSU crystal- induced inflammation program. Targeting CD38 and NAD+ are potentially novel selective molecular approaches to limit gouty arthritis.
2024-05-08 | GSE214587 | GEO
Project description:As a prominent feature of gout, monosodium urate (MSU) crystal deposition can induce gout flare, yet its impact on blood immune in gout remission patients still remains unclear. In this study, single-cell RNA sequencing (scRNA-seq) is used to compare the gene expression profiling of peripheral blood mononuclear cells (PBMCs) among intercritical gout remission patients, advanced gout remission patients and healthy volunteers. The increase of HLA-DQA1high classical monocytes, and their important role in immune inflammatory responses and osteoclast differentiation are discovered in advanced gout remission patients. Moreover, the differentiation level of CD8+T cells are found to elevate in advanced gout remission patients, which is further validated via flow cytometry. It is also observed that pathways related to bone metabolism and inflammatory responses are overactive in advanced gout remission patients. By analysis on intercellular communication network, immune-related cell-cell interactions among PBMCs are shown to enhance in both intercritical and advanced gout remission patients. The analyses on gene expression and LC-MS/MS together indicate the increased metabolic level of arachidonic acid in gout remission patients with MSU deposition at the intercritical and advanced stage. The study reveals distinctive blood immune characteristics in gout remission with MSU deposition, which provides more sights into its pathogenesis.
2023-06-01 | GSE217561 | GEO
Project description:Transcriptomic analysis of primed synovial fibroblasts from monosodium urate crystal-induced arthritis in the mouse
| PRJNA714965 | ENA