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

Abstract：

: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® 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-α 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-κBp65 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.

journal_name

Int Immunopharmacol

journal_title

International immunopharmacology

authors

Wang J,Li R,Lin H,Qiu Q,Lao M,Zeng S,Wang C,Xu S,Zou Y,Shi M,Liang L,Xu H,Xiao Y

doi

10.1016/j.intimp.2019.105791

subject

Has Abstract

pub_date

2019-11-01 00:00:00

pages

105791

eissn

1567-5769

issn

1878-1705

pii

S1567-5769(19)30431-X

journal_volume

pub_type

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