Knockout of SLAMF8 attenuates collagen-induced rheumatoid arthritis in mice through inhibiting TLR4/NF-κB signaling pathway

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial hyperplasia, cartilage damage, and ultimate bone destruction. The signaling lymphocytic activation molecule family member 8 (SLAMF8) is a cell surface receptor expressed on various immune cells. This study aimed to investigate the role of SLAMF8 in the pathogenesis of RA. The SLAMF8 gene was identified as a differentially expressed gene in RA by analyzing the Gene Expression Omnibus database and synovial tissue samples collected from RA patients. Upregulation of SLAMF8 was associated with increased disease activity and inflammation in RA. Mice with collagen type II-induced arthritis (CIA) showed highly expressed SLAMF8, severe paw swelling, elevated inflammatory cytokine production, and excessive accumulation of immune cells. However, knockout of SLAMF8 alleviated collagen type II immunization-induced synovial hyperplasia and joint arthritis in mice. The in-vitro and in-vivo study showed that genetic deletion of SLAMF8 significantly inhibited upregulation of Toll-like receptor 4 (TLR4) and activation of the nuclear factor kappa B (NF-κB) pathway in fibroblast-like synoviocytes and bone marrow-derived macrophages derived from WT and SLAMF8 knockout mice under lipopolysaccharide stimulation. In conclusion, SLAMF8 was aberrantly expressed in RA patient and played an indispensable role in initiating inflammation and maintaining the pro-inflammatory environment in the inflamed joint. Targeted inhibition of SLAMF8 attenuated the severity of RA via blocking the TLR4/NF-κB signaling pathway. These data suggested that SLAMF8 may be a potential target for the treatment of RA.

Keywords: Collagen-induced arthritis; Nuclear factor kappa B; Rheumatoid arthritis; Signaling lymphocyte activation molecule; Toll-like receptor 4.