New Study Shows TLR3 Signaling-Induced Interferon-Stimulated Gene 56 Plays a Role in the Pathogenesis of Rheumatoid Arthritis

WASHINGTON, July 29, 2024 (Newswire.com) - A recently published article in Experimental Biology and Medicine (249:4, 2024) titled “TLR3 signaling-induced interferon-stimulated gene 56 plays a role in the pathogenesis of rheumatoid arthritis” highlights a potential target for the development of novel Rheumatoid Arthritis (RA) treatments. The study, led by Dr. Ishibashi, at Hirosaki University Graduate School of Medicine (Japan), reports that interferon-stimulated gene 56 (ISG56) may be involved in the Toll-like receptor 3 (TLR3)/type I IFN/CXCL10 axis, and play a role in RA synovial inflammation.

Rheumatoid arthritis is a systemic autoimmune disease that causes chronic inflammation of synovial joints as well as the cartilage and bones within the joint primarily. Rheumatoid fibroblast-like synoviocytes (RFLS) have an important role in the inflammatory pathogenesis of RA. Therefore, in recent years, RA therapies have focused on FLS targeting. Toll-like receptor 3 (TLR3) is upregulated in RFLS; its activation leads to the production of interferon-β (IFN-β), a type I IFN. IFN-stimulated gene 56 (ISG56) is induced by IFN and is involved in innate immune responses; however, its role in RA remains unknown. The purpose of this study was to investigate the role of TLR3-induced ISG56 in human RFLS.

The study, led by Dr. Ishibashi, reported that under polyinosinic-polycytidylic acid (poly I:C) treatment, ISG56 expression was upregulated in RFLS, and a type I IFN-neutralizing antibody mixture suppressed ISG56 expression. ISG56 knockdown decreased CXCL10 expression. ISG56 was strongly expressed in the synovial cells of patients with RA. TLR3 signaling-induced ISG56 expression in RFLS and type I IFN was involved in ISG56 expression. These findings suggest that ISG56 is involved in the TLR3/type I IFN/CXCL10 axis, which plays an important role in the inflammatory responses in RFLS. 

Dr. Ishibashi said, “This study showed that ISG56 expression is induced in cultured RFLS via the TLR3/type I IFN axis. In addition, it was shown that ISG56 may positively regulate CXCL10 expression, induced by TLR3 activation. Furthermore, ISG56 was upregulated in the synovial joint cells of patients with RA. These results indicate that ISG56 plays a role in RA pathogenesis. Thus, ISG56 may be a potential target for the development of novel RA therapies."

Dr. Goodman, Editor-in-Chief for Experimental Biology and Medicine, said: “Dr. Ishibashi and colleagues have provided compelling evidence that interferon (IFN)-stimulated gene 56 (ISG56) is involved in the TLR3/type I IFN/CXCL10 axis, which plays an important role in the inflammatory responses in rheumatoid fibroblast-like synovitis. Future studies will be needed to determine the  potential of ISG56 as a therapeutic target for RA treatments.”

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Source: Experimental Biology and Medicine