Ligation of TLR5 promotes myeloid cell infiltration and differentiation into mature osteoclasts in RA and experimental arthritis

摘要

The aim was to examine the impact of TLR5 ligation in rheumatoid arthritis (RA) and experimental arthritis pathology. Studies were conducted to investigate the role of TLR5 ligation on RA and mouse myeloid cell chemotaxis or osteoclast formation; in addition, to uncover the significance of TNF-α function in TLR5 mediated pathogenesis. Next, the in vivo mechanism of action was determined in collagen induced arthritis (CIA) and local joint TLR5 ligation models. Last, to evaluate the importance of TLR5 function in RA, anti-TLR5 antibody therapy was employed in CIA mice. We show that TLR5 agonist, flagellin, can promote monocyte infiltration and osteoclast maturation directly through myeloid TLR5 ligation and indirectly via TNF-α production from RA and mouse cells. These two identified TLR5 functions are potentiated by TNF-α, as inhibition of both pathways can more strongly impair RA synovial fluid driven monocyte migration and osteoclast differentiation compared to each factor alone. In preclinical studies, flagellin post onset treatment in CIA and local TLR5 ligation in vivo, provoke homing and osteoclastic development of myeloid cells, which are associated with the TNF-α cascade. Reversely, CIA joint inflammation and bone erosion is alleviated when TLR5 function is blockade. We found that TLR5 and TNF-α pathways are interconnected, as TNF-α is produced by TLR5 ligation in RA myeloid cells, and anti-TNF-α therapy can markedly suppress TLR5 expression in RA monocytes. Our novel findings demonstrate that a direct as well as an indirect mechanism is involved in TLR5 driven RA inflammation and bone destruction.