Overexpression of Toll‐Like Receptor 3 in Spleen is Associated with Experimental Arthritis in Rats

Abstract

This study is to investigate the regulation of Toll-like receptor (TLR) expression in systemic immune reactions in different arthritis rat models, which will provide evidence to understand the mechanisms of rheumatoid arthritis further. Arthritis-susceptible DA rats were used to induce arthritis by pristane or collagen type II, and TLR2, 3, 4 and 7 expression levels in spleen were detected by real-time quantitative polymerase chain reaction. TLR3 mRNA expression in spleen of both collagen-induced arthritis and pristane-induced arthritis (PIA) rats was increased significantly at 26 and 70 days after arthritis induction. The overexpression of TLR3 was confirmed by Western blotting. Methotrexate was administrated peritoneally to PIA rats, and phytol was applied subcutaneously to PIA rats. Both methotrexate and phytol treatment could alleviate arthritis severity and block TLR3 induction. However, in arthritis-resistant E3 rats injected with pristane, TLR3 expression of spleen was unaltered. PIA in MHC congenic DA.1U rats had mild symptoms, whereas TLR3 mRNA expression in spleen of DA.1U rats showed an impaired induction at D26. So we conclude that overexpression of splenic TLR3 is strongly associated with arthritis in rats, which suggests that TLR3 should be a most vital TLR in spleen to regulate the initiation and development of experimental arthritis and may be as an intriguing therapeutic opportunity for human rheumatoid arthritis.

MicroRNA-26a negatively regulates toll-like receptor 3 expression of rat macrophages and ameliorates pristane induced arthritis in rats

“…TLR3, like other TLRs, has long been considered remarkably conserved across the taxonomic kingdoms and constitutively expressed by numerous immune cells [13], even though studies on regulation of the TLR3 signaling pathway have been widely performed [11,14-16]. Our study and others have shown that TLR3 expression per se changes dramatically under certain scenarios and regulation to its expression is a means to prevent the excess production of proinflammatory cytokines from its overactivated signaling pathway.…”

“…The activated TLR3 pathway could further promote RASFs sustaining B cell activation in the synovium [9]. In the previous study, we found that both TLR3 mRNA and protein expressions are prominently upregulated in splenic macrophages in rats with pristine-induced arthritis (PIA) and collagen-induced arthritis (CIA), and downregulation of TLR3 expression modulates the severity of arthritis [10,11]. TLR3 in the synovium of PIA rats is also overexpressed in an early and persistent style and the activation of the TLR3 signaling pathway in vivo could aggravate PIA [12].…”

Pristane primed rat T cells enhance TLR3 expression of fibroblast-like synoviocytes via TNF-α initiated p38 MAPK and NF-κB pathways

“…And the ability of dsRNA triggering arthritis was related to the function of macrophage secreting type I interferon, and also depended on type I interferon signaling [15]. Our previous studies also showed that PIA in rats relied on TLR3 and its downstream cytokines [4,17]. TLR3 ligands were shown to stimulate DC from RA patients to secrete IL-12, MIF [10,18].…”

Gene/environment interactions in the pathogenesis of autoimmunity: New insights on the role of Toll-like receptors

“…A significant TLR3 up-regulation has been observed in splenocytes in the rat pristane-induced arthritis (PIA) model upon pristane treatment and stimulation of TLR3 with poly-I:C. Accordingly, TLR3 inhibition by using small interfering RNA (siRNA) ameliorated RA in this animal model [111]. The treatment with methotrexate (MTX) inhibited RA symptoms and induced TLR3 over-expression in splenocytes from PIA and collagen-induced arthritis (CIA) rat models [112]. Contrasting data emerged from the study conducted by Yarilina and colleagues [113], where it was demonstrated that TLR3 activation inhibited arthritis in CIA and K/BxN serum transfer models.…”