Accumulation of cytosolic dsDNA contributes to fibroblast-like synoviocytes-mediated rheumatoid arthritis synovial inflammation

Wang, Jingnan; Li, Ruiru; Lin, Haobo; Qiu, Qian; Lao, Minxi; Zeng, Shan; Wang, Cuicui; Xu, Siqi; Zou, Yaoyao; Shi, Maohua; Liang, Liuqin; Xu, Hanshi; Xiao, Youjun

doi:10.1016/j.intimp.2019.105791

Cited by 53 publications

(38 citation statements)

References 29 publications

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“…Under TNF-α stimulation, cGAS was overexpressed in RA-FLS and enhanced the production of inflammatory cytokines and Akt, promoted the phosphorylation of extracellular signal-regulated protein kinase (ERK) [82]. Furthermore, the accumulation of cytosolic DNA promoted an inflammatory response via the cGAS-STING pathway in RA FLS [83]. Recognition of self-DNA by DNA sensing receptors.…”

Section: Tlr9 and Cgasmentioning

confidence: 99%

Cell-Free DNA in Rheumatoid Arthritis

Hashimoto

Yoshida

Hashiramoto

2021

IJMS

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Endogenous DNA derived from the nuclei or mitochondria is released into the bloodstream following cell damage or death. Extracellular DNA, called cell-free DNA (cfDNA), is associated with various pathological conditions. Recently, multiple aspects of cfDNA have been assessed, including cfDNA levels, integrity, methylation, and mutations. Rheumatoid arthritis (RA) is the most common form of autoimmune arthritis, and treatment of RA has highly varied outcomes. cfDNA in patients with RA is elevated in peripheral blood and synovial fluid and is associated with disease activity. Profiling of cfDNA in patients with RA may then be utilized in various aspects of clinical practice, such as the prediction of prognosis and treatment responses; monitoring disease state; and as a diagnostic marker. In this review, we discuss cfDNA in patients with RA, particularly the sources of cfDNA and the correlation of cfDNA with RA pathogenesis. We also highlight the potential of analyzing cfDNA profiles to guide individualized treatment approaches for RA.

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Section: Tlr9 and Cgasmentioning

confidence: 99%

Cell-Free DNA in Rheumatoid Arthritis

Hashimoto

Yoshida

Hashiramoto

2021

IJMS

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“…An example is the predictive pfcHap STING1_1.0 (HAQ) (Table 1) which comprises 3 nonsynonymous SNPs (rs7380824 (R71H), rs78233829 (G230A), rs11554776 (R293Q)) within the STING1 (Stimulator of Interferon Gene 1) gene that was involved in both MTX and RA (Figure S2). Specifically, STING1 is implicated in the cGAS-STING pathway that contributes to inflammatory response in RA, 67 and MTX has been reported to inhibit the activation of STING and downstream effects. 68 Individuals harbouring the HAQ haplotype of the predictive pfcHap STING1_1.0 were previously reported to be more susceptible to viral infection and less responsive to DNA vaccines.…”

Section: Articlesmentioning

confidence: 99%

Functional coding haplotypes and machine-learning feature elimination identifies predictors of Methotrexate Response in Rheumatoid Arthritis patients

Lim

Ooi

et al. 2022

eBioMedicine

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Background Major challenges in large scale genetic association studies include not only the identification of causative single nucleotide polymorphisms (SNPs), but also accounting for SNP-SNP interactions. This study thus proposes a novel feature engineering approach integrating potentially functional coding haplotypes (pfcHap) with machine-learning (ML) feature selection to identify biologically meaningful, possibly causative genetic factors, that take into consideration potential SNP-SNP interactions within the pfcHap, to best predict for methotrexate (MTX) response in rheumatoid arthritis (RA) patients.Methods Exome sequencing from 349 RA patients were analysed, of which they were split into training and unseen test set. Inferred pfcHaps were combined with 30 non-genetic features to undergo ML recursive feature elimination with cross-validation using the training set. Predictive capacity and robustness of the selected features were assessed using six popular machine learning models through a train set cross-validation and evaluated in an unseen test set.Findings Significantly, 100 features (95 pfcHaps, 5 non-genetic factors) were identified to have good predictive performance (AUC: 0.776-0.828; Sensitivity: 0.656-0.813; Specificity: 0.684-0.868) across all six ML models in an unseen test dataset for the prediction of MTX response in RA patients.Interpretation Majority of the predictive pfcHap SNPs were predicted to be potentially functional and some of the genes in which the pfcHap resides in were identified to be associated with previously reported MTX/RA pathways.

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“…Interestingly, dsDNA from RA synovial fluid can induce joint inflammation in vivo (5). Our previous study also demonstrated that the accumulation of cytosolic dsDNA in RA FLSs contributes to the inflammatory response (6). Cyclic guanosine monophosphateadenosine monophosphate (GMP-AMP) synthase (cGAS), which serves as a key cytosolic DNA sensor, activates the stimulator of interferon genes (STING), thereby promoting type I interferon (IFN) production and causing an inflammatory response in turn (4).…”

Section: Introductionmentioning

confidence: 99%

“…Cyclic guanosine monophosphateadenosine monophosphate (GMP-AMP) synthase (cGAS), which serves as a key cytosolic DNA sensor, activates the stimulator of interferon genes (STING), thereby promoting type I interferon (IFN) production and causing an inflammatory response in turn (4). Our previous study showed that the accumulation of cytosolic dsDNA induces cGAS/STING activation, which promotes the proinflammatory cytokine secretion in RA FLSs, suggesting an important role for cytosolic dsDNA-mediated cGAS/ STING activation in rheumatoid synovial inflammation (6). Interestingly, recent studies have indicated that cGAS/ STING pathway activation is involved in modulating migration, invasion, and proliferation in some cell lines (7,8).…”

Section: Introductionmentioning

confidence: 99%

cGAS/STING signaling in the regulation of rheumatoid synovial aggression

Li¹,

Lin²,

Yu³

et al. 2022

Ann Transl Med

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Background: Fibroblast-like synoviocytes (FLSs) play a critical role in promoting synovial aggression and joint destruction in rheumatoid arthritis (RA). Cyclic GMP-AMP synthase (cGAS)/stimulator of interferon gene (STING) signaling plays an important role in controlling a series of cellular biological processes. However, it is still unclear whether cGAS/STING signaling regulates rheumatoid synovial aggression.Methods: Cell migration and invasion were detected using a Transwell chamber. Gene expression was measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and protein expression was detected by western blotting. Reactive oxygen species (ROS) levels were measured by 2',7'-di chlorodihydrofluorescein diacetate (DCFH-DA) probe. F-actin staining and immunofluorescence assays were used to investigate lamellipodia formation and nuclear translocation, respectively. A severe combined immunodeficiency (SCID) mouse model was established to observe the migration and invasion of RA FLSs in vivo.Results: Our results showed that cytosolic double-stranded DNA (dsDNA)-induced cGAS/STING activation promoted the in vitro migration and invasion of RA FLSs. Moreover, RA FLSs treated with cGAS or STING short hairpin RNA (shRNA) exhibited reduced invasion into cartilage in the SCID model.Mechanistically, we determined that cGAS/STING activation leads to increased mitochondrial ROS levels, and thereby increases phosphorylation of mammalian sterile 20-like kinase 1 (MST1), a core component of the Hippo pathway, subsequently promoting activation of forkhead box1 (FOXO1). MST1 and FOXO1 knockdown also diminished the migration and invasion of RA FLSs.Conclusions: Our findings suggest that cGAS/STING signaling has an important role in regulating rheumatoid synovial aggression and that targeting cGAS/STING may represent a novel potential therapy for RA.

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Accumulation of cytosolic dsDNA contributes to fibroblast-like synoviocytes-mediated rheumatoid arthritis synovial inflammation

Cited by 53 publications

References 29 publications

Cell-Free DNA in Rheumatoid Arthritis

Cell-Free DNA in Rheumatoid Arthritis

Functional coding haplotypes and machine-learning feature elimination identifies predictors of Methotrexate Response in Rheumatoid Arthritis patients

cGAS/STING signaling in the regulation of rheumatoid synovial aggression

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