Contribution of MyD88-dependent PKD1 to the development of arthritis (THER2P.954)

Abstract

Abstract Rheumatoid arthritis (RA) may be initiated in part by signaling through Toll-like receptors (TLRs). Disruption of TLR signaling may provide an opportunity to halt the RA process in the earliest stages. We investigated whether protein kinase D1 (PKD1), which is essential for proinflammatory responses mediated by MyD88-dependent TLRs, plays a role in the development of experimental arthritis. The presence of TLR ligands in joint cavities induces development of reactive arthritis that is characterized by accumulation of activated inflammatory cells in the joints. Deletion of PKD1 in myeloid lineage cells prevented TLR-mediated accumulation of inflammatory cells in joints, thus protecting mice from developing reactive arthritis. Arthritis spontaneously occurring in IL-1R antagonist-deficient (IL-1rn-/-) mice was dependent on MyD88, and suppression of PKD1 expression resulted in inhibition of TLR-mediated cytokine production in IL-1rn-/- macrophages. Daily treatment with a PKD inhibitor substantially reduced the incidence and severity of arthritis in IL-1rn-/- mice. In addition, a PKD inhibitor inhibited the synergistic effect of T cell receptor and TLR2 on IL-6 production in splenocytes, and significantly reduced the incidence and severity of collagen-induced arthritis that closely mimics the pathophysiologic process of human RA. This implies that PKD1 might be one of the key factors that modulate proinflammatory responses in RA, and can be a therapeutic target for RA.