Blocking the Sphingosine-1-Phosphate Receptor 2 (S1P₂) Reduces the Severity of Collagen-Induced Arthritis in DBA-1J Mice

The amount of sphingosine 1-phosphate (S1P) found in the synovial tissue of individuals with rheumatoid arthritis is five times greater than that in those with osteoarthritis. Our study aims to determine whether inhibiting S1P₂ can mitigate collagen-induced rheumatoid arthritis (CIA) by using an S1P₂ antagonist, JTE-013, alongside DBA-1J S1pr2 wild-type (WT) and knock-out (KO) mice. CIA causes increases in arthritis scores, foot swelling, synovial hyperplasia, pannus formation, proteoglycan depletion, cartilage damage, and bone erosion, but these effects are markedly reduced when JTE-013 is administered to S1pr2 WT mice. CIA also elevates mRNA expression levels of pro-inflammatory Th1/Th17 cytokines in the foot and spleen, which are significantly decreased by JTE-013 in S1pr2 WT mice. Additionally, CIA raises Th1/Th17 and Treg cell counts, while JTE-013 reduces these elevations in the spleens of S1pr2 WT mice. Treatment with JTE-013 or the absence of S1pr2 curtails the differentiation of naïve T cells into Th1 and Th17 cells in a dose-dependent manner. In SW982 human synovial cells, JTE-013 lowers LPS-induced increases in pro-inflammatory cytokine levels. Overall, these findings propose that blocking S1P₂ in immune and synovial cells may alleviate rheumatoid arthritis symptoms and offer a potential therapeutic approach.