Systematic analysis of inflammation and pain pathways in a mouse model of gout
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ABSTRACT:
PROVIDER: PRJNA785977 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17120842_1.fastq.gz | Fastqsanger.gz | |||
| SRR17120842_2.fastq.gz | Fastqsanger.gz | |||
| SRR17120843_1.fastq.gz | Fastqsanger.gz | |||
| SRR17120843_2.fastq.gz | Fastqsanger.gz | |||
| SRR17120844_1.fastq.gz | Fastqsanger.gz |
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Project description:Gout is a prevalent and painful inflammatory arthritis, and its global burden continues to rise. Intense pain induced by gout attacks is a major complication of gout. However, systematic studies of gout inflammation and pain are lacking. Using a monosodium urate (MSU) crystal-induced gout model, we performed genome-wide transcriptome analysis of the inflamed ankle joint, dorsal root ganglion (DRG), and spinal cord of gouty mice. Our results revealed important transcriptional changes, including highly elevated inflammation and broad activation of immune pathways in both the joint and the nervous system, in gouty mice. Integrated analysis showed that there was a remarkable overlap between our RNAseq and human genome-wide association study (GWAS) of gout; for example, the risk gene, stanniocalcin-1 (STC1) showed significant upregulation in all three tissues. Interestingly, when compared to the transcriptomes of human osteoarthritis (OA) and rheumatoid arthritis (RA) joint tissues, we identified significant upregulation of cAMP/cyclic nucleotide-mediated signaling shared between gouty mice and human OA with high knee pain, which may provide excellent drug targets to relieve gout pain. Furthermore, we investigated the common and distinct transcriptomic features of gouty, inflammatory pain, and neuropathic pain mouse models in their DRG and spinal cord tissues. Moreover, we discovered distinct sets of genes with significant differential alternative splicing or differential transcript usage in each tissue, which were largely not detected by conventional differential gene expression analysis approaches. Based on these results, our study provided a more accurate and comprehensive depiction of transcriptomic alterations related to gout inflammation and pain.
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Project description:To determine the expression profile and clinical significance of circular RNAs (circRNAs) in peripheral blood mononuclear cells (PBMCs) of patients with primary gout and healthy control subjects. Human circRNA microarrays were used to identify the differentially expressed circRNAs in primary gout (Gout, n = 5) and healthy subjects (HC, n = 3). Bioinformatics analyses were performed to predict the roles of differently expressed circRNAs. Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to validate the results in 90 gout patients, and 60 healthy control subjects (HC). Microarray analysis indicated that 238 circRNAs were up-regulated and 41 circRNAs were down-regulated in the Gout group (Fold change>1.5, p-value<0.05). Bioinformatics analysis showed that differentially expressed circRNAs were involved in the pathogenesis of gout through a variety of different pathways. Significant association was observed between these circRNAs and lipid metabolism indicators. Our results provide novel insight into the mechanisms of primary gout, and reveal that hsa_circRNA_103657 could effectively discriminate the gout group and the healthy control groups.
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Project description:Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of pro-inflammatory cytokines, including interleukin-1 beta (IL-1B). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1B, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177,824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] ≥2%: OR, 1.69; 95% CI, 1.09-2.61; P=0.0189; UKB, CHIP with VAF ≥10%: OR, 1.25; 95% CI, 1.05-1.50; P=0.0133). Moreover, individuals with CHIP and a VAF ≥10% had an increased risk of incident gout (UKB: HR, 1.28; 95% CI, 1.06-1.55; P=0.0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1B secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1B in response to MSU crystals in vitro, and this was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1B levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in gout patients.
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