Abstract
C-X-C motif chemokine 10 (CXCL10) is an inflammatory chemokine and a key molecule in the pathogenesis of rheumatoid arthritis (RA). Melanoma differentiation-associated gene 5 (MDA5) is an RNA helicase that plays a role in innate immune and inflammatory reactions. The details of the regulatory mechanisms of CXCL10 production and the precise role of MDA5 in RA synovitis have not been fully elucidated. The aim of this study was to examine the role of MDA5 in regulating CXCL10 expression in cultured human rheumatoid fibroblast-like synoviocytes (RFLS). RFLS was stimulated with Toll-like receptor 3 (TLR3) ligand polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA mimetic. Expression of interferon beta (IFN-β), MDA5, and CXCL10 was measured by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, and enzyme-linked immunosorbent assay. A neutralizing antibody of IFN-β and siRNA-mediated MDA5 knockdown were used to determine the role of these molecules in regulating CXCL10 expression downstream of TLR3 signaling in RFLS. Poly I:C induced IFN-β, MDA5, and CXCL10 expression in a concentration- and time-dependent manner. IFN-β neutralizing antibody suppressed the expression of MDA5 and CXCL10, and knockdown of MDA5 decreased a part of CXCL10 expression (p < 0.001). The TLR3/IFN-β/CXCL10 axis may play a crucial role in the inflammatory responses in RA synovium, and MDA5 may be partially involved in this axis.
Highlights
Rheumatoid arthritis (RA) is a common chronic inflammatory autoimmune disease that reduces quality of life [1]
I:C induces the expression of IFN‐β, Melanoma differentiation-associated gene 5 (MDA5), and CXCL10 in rheumatoid fibroblast-like synoviocytes (RFLS)
We have demonstrated that the activation of Toll-like receptor 3 (TLR3) signaling in RFLS upregulated IFN-β, MDA5, and CXCL10 expression
Summary
Rheumatoid arthritis (RA) is a common chronic inflammatory autoimmune disease that reduces quality of life [1]. Common characteristics of RA include infiltration of macrophages and lymphocytes, synovitis, and destruction of bone and cartilage [4]. An essential step in the pathogenesis of RA is the infiltration of the synovium by immune cells, which causes synovitis [5]. The fibroblast-like synoviocytes are critical cells in the pathogenesis of RA. The innate immune system is the first line of protection against pathogenic microorganisms. The innate immune system is activated by pattern-recognition receptors that recognize pathogen-associated molecular patterns (PAMPs). In addition to PAMPs, damage-associated molecular patterns (DAMPs) released from dead and/or stressed cells can be recognized by pattern-recognition receptors. DAMPs may induce sterile inflammation in the absence of infection and plays an important role in the pathogenesis of autoimmune diseases [7]
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