High efficacy of Toll-like receptor 4 targeting in murine and humanized models of rheumatoid arthritis in comparison with IL-1 and TNF inhibitors (THER6P.860)

Abstract Enhanced expression of Toll-like Receptor (TLR) 4 and its endogenous agonists in rheumatoid joints suggests involvement in rheumatoid arthritis (RA). We assessed therapeutic efficacy and downstream effects of TLR4 blockade in murine and humanized models of RA compared with interleukin-1 (IL-1) and tumor necrosis factor (TNF) inhibitors. TLR4 blockade using purified B. quintana LPS suppressed established collagen-induced arthritis, and reduced serum IL-1β and IL-6 concentrations to the same extent as IL-1 and TNF inhibitors. TLR4 targeting exceeded beneficial effects of TNF blocker by reducing serum TNFα and IL-17 along with synovial expression of IL-23p19, IL-17 and the Th17-related transcription factor RORγt, while Th1 markers and type II collagen-directed T cell proliferation and antibody responses remained unaffected. To translate the findings into human disease, RA synovial biopsies were engrafted into SCID mice. TLR4 inhibition in this model resulted in reduction of spontaneous IL-6 and IL-8 release by RA synovium and reduced synovial inflammation, thereby equaling anti-TNF therapy. In ex vivo cultures of RA synovial explants, high-density protein microarray revealed suppressed activation of multiple key signaling molecules including NFκBp65 phospho-Ser536 (27%), TAK1 phospho-Thr187 and -Ser412 (26 and 23%, resp.), JAK1 phospho-Tyr1022 (22%), IRF3 (51%), Foxo3a (39%) and Btk (24%). The data collectively suggest TLR4 as a potential therapeutic target in RA.