Anti-Arthritic Effect of TLR4 Inhibitor TAK-242 Through the Inhibition of Th1 and Th17 Cell Proliferation in a Curdlan-Induced Spondyloarthritis SKG Mouse Model

Abstract Background: Toll-like receptor 4 (TLR4) is involved in the pathogenesis of arthritic diseases. The TLR4 inhibitor TAK-242 has shown potential as a possible treatment for rheumatoid arthritis in an adjuvant-induced arthritis rat model. However, further investigation of the anti-arthritis effect of TAK-242 in other animal models of arthritis disease is required. Objective: This study was conducted to examine the anti-arthritic effects and mechanisms of TAK-242 on curdlan-induced spondyloarthritis in SKG mice. Methods: Curdlan-injected SKG ZAP-70W163C mice were intraperitoneally administered with TAK-242 (3 mg/kg) every other day or anti-IL-23 antibody (100 μg) weekly for 9 weeks. The therapeutic effect of TAK-242 was evaluated in the SKG mice by measuring the inflammation level of foot, ileum, lung and tail by histology, the levels of proinflammatory cytokines in serum, bone mineral density (BMD) in femur and spine, and CD4+T cell subtypes Th1 and Th17 in spleen.Results: TAK-242 treatment significantly reduced clinical score, paw width, and colon length in SKG mice. Consistent with the therapeutic effect, TAK-242 also reduced peripheral arthritis and IL-17 expression in the foot and ileum tissues. It also inhibited inflammation of the lungs, ileum, paws, and tail and reduced serum levels of pro-inflammatory cytokines such as IL-6 and TNF-α. TAK-242 recovered the reduced bone density in the femur but not in the spine. Treatment with TAK-242 also suppressed the populations of Th1 and Th17 cells in the spleen of SKG mice.Conclusions: TAK-242 may show beneficial anti-arthritis effects by inhibiting the proliferation of pro-inflammatory Th1 and Th17 cells. Further research is needed for TAK-242 to be repositioned as a treatment for arthritis disease.