Upregulation of sphingosine-1-phosphate receptor 3 on fibroblast-like synoviocytes is associated with the development of collagen-induced arthritis via increased interleukin-6 production

Abstract

Background Sphingosine-1-phosphate receptor 3 (S1P 3 ) is one of five receptors for sphingosine-1-phosphate (S1P). S1P/S1P 3 signaling is involved in numerous physiological and pathological processes including bone metabolism, sepsis, cancer, and immunity. In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLSs) are activated by several factors and promote abundant proinflammatory cytokine production and bone destruction. The aim of this study was to investigate whether S1P 3 is associated with the development of autoimmune arthritis and the pathogenic function of FLSs. Methods Wild-type (WT) and S1P 3 knockout (S1P 3 -KO) collagen-induced arthritis (CIA) mice were evaluated with respect to clinical and histological disease severity, along with the levels of anti-collagen antibodies and expression of tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6). S1P 3 expression in the synovium was analyzed by real-time reverse-transcription polymerase chain reaction (RT-PCR) and immunofluorescence staining. FLSs isolated from CIA mice were activated with TNFα and S1P 3 expression was analyzed by real-time RT-PCR. The role of S1P/S1P 3 signaling in activated and non-activated FLSs was investigated by measuring cell proliferation and cyto/chemokine production by real-time RT-PCR and/or enzyme-linked immunosorbent assay. Results Clinical and histological scores, and synovial IL-6 expression were significantly lower in S1P 3 -KO mice with CIA than in WT mice. Arthritic synovia had higher S1P 3 expression than intact synovia and FLSs in arthritic joints expressed S1P 3 in vivo . Primary cultured FLSs produced IL-6 in a time-dependent manner in response to S1P stimulation and exhibited higher levels of S1P 3 expression after activation with TNFα. S1P 3 -induced production of IL-6 and MMP-3 was increased in FLSs pre-activated with TNFα. Conclusion In this study, we demonstrated that S1P 3 expression is associated with the development of autoimmune arthritis via inflammation-induced increases in S1P/S1P 3 signaling that increase production of IL-6 in FLSs. Inhibition of S1P/S1P 3 signaling could open the door to the development of new therapies for RA.

S1P promotes IL-6 expression in osteoblasts through the PI3K, MEK/ERK and NF-κB signaling pathways

“…The factors responsible for initiating the degradation and loss of the articular tissues are largely unknown. Upregulation of S1P has been found in synovial tissues of the collagen-induced arthritis model [20]. However, little is known about the role of S1P in the expression of the critical inflammatory cytokine IL-6 and RA development.…”

“…Interestingly, deleting the S1P2 receptor promotes murine embryonic fibroblast migration towards S1P and also PDGF, which stimulates S1P production; S1P 2 deletion also increases the enzymatic expression and activity of sphingosine kinase 1 (SphK1), which is responsible for producing S1P [18]. In addition, S1P/S1P 1 signaling reportedly regulates osteoimmunology [19] and upregulation of the S1P receptor in synovial tissues has found in the collagen-induced arthritis model [20]. However, the role of S1P in IL-6 expression and RA pathogenesis is uncertain.…”

A bioavailable form of curcumin, in combination with vitamin-D- and omega-3-enriched diet, modifies disease onset and outcomes in a murine model of collagen-induced arthritis

“…In this study, we showed that bioavailable CUR by itself suppresses the abundance of several MMPs, including MMP-3, in the joints of CIA mice. It is known that MMP-3 promotes the pathology of RA, is enhanced in RA patients [ 70 ], and associated with the development of RA [ 71 , 72 ]. Previous studies have demonstrated that CUR targets the mTOR pathways to intervene in the production of MMP-3 in a CIA rat model [ 10 ] and downregulates MMP-3 to inhibit proliferation of synovial cells [ 73 ].…”

Recent advances of the function of sphingosine 1‐phosphate (S1P) receptor S1P3

“…The reduction of CIA in S1P3KO mice exhibited an association with the reduction of IL‐6 produced by FLSs, which was activated by S1P3. The inhibition of the S1P/S1P3 signaling pathway is thus expected to provide new targets for the treatment of rheumatoid arthritis (RA; Inoue et al, 2019). Some research has been conducted to reveal the critical role of dendritic cell protease‐activated receptor 1(PAR1)–S1P3 cross‐talk in regulating the amplification of inflammation in sepsis syndrome (Niessen et al, 2008).…”