Single-cell transcriptomics reveals variations in monocytes and Tregs between gout flare and remission.
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ABSTRACT:
SUBMITTER: Yu H
PROVIDER: S-EPMC10967374 | biostudies-literature | 2024 Feb
REPOSITORIES: biostudies-literature
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Single-cell transcriptomics reveals variations in monocytes and Tregs between gout flare and remission.
Yu Hanjie H Xue Wen W Yu Hanqing H Song Yaxiang Y Liu Xinying X Qin Ling L Wang Shu S Bao Hui H Gu Hongchen H Chen Guangqi G Zhao Dake D Tu Yang Y Cheng Jiafen J Wang Liya L Ai Zisheng Z Hu Dayong D Wang Ling L Peng Ai A
JCI insight 20240208 3
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Project description:Gout commonly manifests as a painful, self-limiting inflammatory arthritis. Nevertheless, the understanding of the inflammatory and immune responses underlying gout flares and remission remains ambiguous. Here, based on single-cell RNA-Seq and an independent validation cohort, we identified the potential mechanism of gout flare, which likely involves the upregulation of HLA-DQA1+ nonclassical monocytes and is related to antigen processing and presentation. Furthermore, Tregs also play an essential role in the suppressive capacity during gout remission. Cell communication analysis suggested the existence of altered crosstalk between monocytes and other T cell types, such as Tregs. Moreover, we observed the systemic upregulation of inflammatory and cytokine genes, primarily in classical monocytes, during gout flares. All monocyte subtypes showed increased arachidonic acid metabolic activity along with upregulation of prostaglandin-endoperoxide synthase 2 (PTGS2). We also detected a decrease in blood arachidonic acid and an increase in leukotriene B4 levels during gout flares. In summary, our study illustrates the distinctive immune cell responses and systemic inflammation patterns that characterize the transition from gout flares to remission, and it suggests that blood monocyte subtypes and Tregs are potential intervention targets for preventing recurrent gout attacks and progression.
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Project description:Gout typically presents as an acute, self-limiting inflammatory monoarthritis. Based on single-cell RNA sequencing (scRNA-seq), we profiled peripheral blood mononuclear cells (PBMCs) from the same patients with gout flare and gout remission We identified the dynamics of cell abundance, gene expression patterns and biological processes underlying the immune dysregulation of each cell compartment. The single-cell landscape of both innate and adaptive immune responses provides new insights into pathogenesis and therapy of gout flare.
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Project description:ImportanceGout is associated with cardiovascular diseases. The temporal association between gout flares and cardiovascular events has not been investigated.ObjectiveTo investigate whether there is a transient increase in risk of cardiovascular events after a recent gout flare.Design, setting, and participantsA retrospective observational study was conducted using electronic health records from the Clinical Practice Research Datalink in England between January 1, 1997, and December 31, 2020. A multivariable nested case-control study was performed among 62 574 patients with gout, and a self-controlled case series, adjusted for season and age, was performed among 1421 patients with gout flare and cardiovascular event.ExposuresGout flares were ascertained using hospitalization, primary care outpatient, and prescription records.Main outcomes and measuresThe primary outcome was a cardiovascular event, defined as an acute myocardial infarction or stroke. Association with recent prior gout flares was measured using adjusted odds ratios (ORs) with 95% CIs in a nested case-control study and adjusted incidence rate ratios (IRRs) with 95% CIs in a self-controlled case series.ResultsAmong patients with a new diagnosis of gout (mean age, 76.5 years; 69.3% men, 30.7% women), 10 475 patients with subsequent cardiovascular events were matched with 52 099 patients without cardiovascular events. Patients with cardiovascular events, compared with those who did not have cardiovascular events, had significantly higher odds of gout flare within the prior 0 to 60 days (204/10 475 [2.0%] vs 743/52 099 [1.4%]; adjusted OR, 1.93 [95% CI, 1.57-2.38]) and within the prior 61 to 120 days (170/10 475 [1.6%] vs 628/52 099 [1.2%]; adjusted OR, 1.57 [95% CI, 1.26-1.96]). There was no significant difference in the odds of gout flare within the prior 121 to 180 days (148/10 475 [1.4%] vs 662/52 099 [1.3%]; adjusted OR, 1.06 [95% CI, 0.84-1.34]). In the self-controlled case series (N = 1421), cardiovascular event rates per 1000 person-days were 2.49 (95% CI, 2.16-2.82) within days 0 to 60; 2.16 (95% CI, 1.85-2.47) within days 61 to 120; and 1.70 (95% CI, 1.42-1.98) within days 121 to 180 after a gout flare, compared with cardiovascular event rates of 1.32 (95% CI, 1.23-1.41) per 1000 person-days within the 150 days before or the 181 to 540 days after the gout flare. Compared with 150 days before or the 181 to 540 days after a gout flare, incidence rate differences for cardiovascular events were 1.17 (95% CI, 0.83-1.52) per 1000 person-days, and adjusted IRRs were 1.89 (95% CI, 1.54-2.30) within days 0 to 60; 0.84 (95% CI, 0.52-1.17) per 1000 person-days and 1.64 (95% CI, 1.45-1.86) within days 61 to 120; and 0.38 (95% CI, 0.09-0.67) per 1000 person-days and 1.29 (95% CI, 1.02-1.64) within days 121 to 180 after a gout flare.Conclusions and relevanceAmong individuals with gout, those who experienced a cardiovascular event, compared with those who did not experience such an event, had significantly higher odds of a recent gout flare in the preceding days. These findings suggest gout flares are associated with a transient increase in cardiovascular events following the flare.
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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.
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Project description:Immune-mediated inflammatory diseases (IMIDs) are typically characterised by relapsing and remitting flares of inflammation. However, the unpredictability of disease flares impedes their study. Addressing this critical knowledge gap, we use the experimental medicine approach of immunomodulatory drug withdrawal in rheumatoid arthritis (RA) remission to synchronise flare processes allowing detailed characterisation. Exploratory mass cytometry analyses reveal three circulating cellular subsets heralding the onset of arthritis flare - CD45RO+PD1hi CD4+ and CD8+ T cells, and CD27+CD86+CD21- B cells - further characterised by single-cell sequencing. Distinct lymphocyte subsets including cytotoxic and exhausted CD4+ memory T cells, memory CD8+CXCR5+ T cells, and IGHA1+ plasma cells are primed for activation in flare patients. Regulatory memory CD4+ T cells (Treg cells) increase at flare onset, but with dysfunctional regulatory marker expression compared to drug-free remission. Significant clonal expansion is observed in T cells, but not B cells, after drug cessation; this is widespread throughout memory CD8+ T cell subsets but limited to the granzyme-expressing cytotoxic subset within CD4+ memory T cells. Based on our observations, we suggest a model of immune dysregulation for understanding RA flare, with potential for further translational research towards novel avenues for its treatment and prevention.
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