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首页> 外文期刊>International immunopharmacology >Accumulation of cytosolic dsDNA contributes to fibroblast-like synoviocytes-mediated rheumatoid arthritis synovial inflammation
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Accumulation of cytosolic dsDNA contributes to fibroblast-like synoviocytes-mediated rheumatoid arthritis synovial inflammation

机译：细胞溶质DSDNA的积累有助于成纤维细胞样的滑膜细胞介导的类风湿性关节炎滑膜炎症

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摘要

The accumulation of cytosolic dsDNA plays important roles in the regulation of cellular processes. However, whether cytosolic dsDNA is involved in the pathogenesis of rheumatoid arthritis (RA) is not clear. Therefore, the present study investigated the roles of cytosolic dsDNA in the modulation of inflammatory responses of fibroblast-like synoviocytes (FLS) in patients with RA. FLS were obtained from active RA patients. dsDNA accumulation in the cytosol was detected by immunofluorescence staining and the Qubit (R) dsDNA HS Assay. Immunohistochemistry was employed to detect the dsDNA and cGMP-AMP synthase (cGAS) expression in the synovium. Short hairpin RNA (shRNA) was used to knockdown the expression of cGAS and stimulator of interferon genes (STING). Protein expression was detected by Western blotting and immunofluorescence staining. We observed increased cytosolic dsDNA and cGAS expression in FLS and synovium from RA patients. dsDNA and cGAS expression correlated with the severity of rheumatoid synovitis. Transfection of dsDNA into the cytosol of RA FLS promoted pro-inflammatory cytokines production. DNaseII overexpression downregulated cytosolic dsDNA expression and inhibited dsDNA-induced cytokines secretion. We also found that dsDNA and TNF-alpha enhanced cGAS and STING expression, and dsDNA-induced cytokine secretion was reduced by cGAS or STING knockdown. Furthermore, we determined that the dsDNA-induced phosphorylation of IRF3 and NF-kappa Bp65 was decreased by DNaseII overexpression or cGAS/STING knockdown. Overall, our findings show that increased cytosolic dsDNA level promoted inflammatory responses via the cGAS/STING pathway in RA FLS, which suggests that cytosolic dsDNA accumulation is an important contributor to FLS-mediated rheumatoid synovial inflammation.
机译：细胞溶质DSDNA的积累在细胞过程调节中起重要作用。然而，细胞溶质DSDNA是否参与了类风湿性关节炎（RA）的发病机制尚不清楚。因此，本研究研究了细胞溶质DSDNA在RA患者患者中成纤维细胞样Synoviocytes（FLS）炎症反应的作用。从活性RA患者获得FLS。通过免疫荧光染色和QUBbit（R）DSDNA HS测定检测细胞溶质中的DSDNA积累。使用免疫组织化学来检测滑动中的DSDNA和CGMP-AMP合酶（CGA）表达。使用短发夹RNA（ShRNA）敲击干扰素基因的CGA和刺激剂的表达（Sting）。通过蛋白质印迹和免疫荧光染色来检测蛋白质表达。我们观察到来自RA患者的杂草和Synovium的细胞溶质DSDNA和CGA表达增加。 DSDNA和CGA表达与类风湿性滑膜炎的严重程度相关。将DSDNA转染到RA FLS的细胞溶胶促进促炎细胞因子的产生。 DNASEII过表达下调的细胞溶质DSDNA表达并抑制DSDNA诱导的细胞因子分泌。我们还发现DSDNA和TNF-α增强的CGA和STING表达，并通过CGA或Sting敲低降低了DSDNA诱导的细胞因子分泌。此外，我们确定DNAseII过表达或CGA /刺痛敲低的DSDNA诱导的IRF3和NF-KAPPA BP65的磷酸化。总体而言，我们的研究结果表明，通过RA FLS中的CGA / Sting途径促进了细胞溶质DSDNA水平的增加促进了炎症反应，这表明细胞溶质DSDNA积累是FLS介导的类风湿性滑膜炎症的重要因素。

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  • 来源
    《International immunopharmacology》 |2019年第2019期|共12页
  • 作者

    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;

  • 作者单位

    Sun Yat Sen Univ Affiliated Hosp 1 Dept Rheumatol &

    Clin Immunol Guangzhou Guangdong Peoples R;

    Sun Yat Sen Univ Affiliated Hosp 1 Dept Rheumatol &

    Clin Immunol Guangzhou Guangdong Peoples R;

    Guangdong Acad Med Sci Guangdong Prov Peoples Hosp Dept Rheumatol Guangzhou Guangdong Peoples;

    Sun Yat Sen Univ Affiliated Hosp 1 Dept Rheumatol &

    Clin Immunol Guangzhou Guangdong Peoples R;

    Sun Yat Sen Univ Affiliated Hosp 1 Dept Rheumatol &

    Clin Immunol Guangzhou Guangdong Peoples R;

    Sun Yat Sen Univ Affiliated Hosp 1 Dept Rheumatol &

    Clin Immunol Guangzhou Guangdong Peoples R;

    Sun Yat Sen Univ Affiliated Hosp 1 Dept Rheumatol &

    Clin Immunol Guangzhou Guangdong Peoples R;

    Sun Yat Sen Univ Affiliated Hosp 1 Dept Rheumatol &

    Clin Immunol Guangzhou Guangdong Peoples R;

    Sun Yat Sen Univ Affiliated Hosp 1 Dept Rheumatol &

    Clin Immunol Guangzhou Guangdong Peoples R;

    Sun Yat Sen Univ Affiliated Hosp 1 Dept Rheumatol &

    Clin Immunol Guangzhou Guangdong Peoples R;

    Sun Yat Sen Univ Affiliated Hosp 1 Dept Rheumatol &

    Clin Immunol Guangzhou Guangdong Peoples R;

    Sun Yat Sen Univ Affiliated Hosp 1 Dept Rheumatol &

    Clin Immunol Guangzhou Guangdong Peoples R;

    Sun Yat Sen Univ Affiliated Hosp 1 Dept Rheumatol &

    Clin Immunol Guangzhou Guangdong Peoples R;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;
  • 关键词

    Cytosolic dsDNA; Inflammation; cGAS; FLS; Rheumatoid arthritis;

    机译：细胞溶质dsdna;炎症;cgas;vs;类风湿性关节炎;

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