MyD88-dependent PKD1 is essential for development of polyarthritis spontaneously occurring in IL-1R antagonist-deficient mice.

Abstract

Abstract IL-1 receptor antagonist-deficient (IL-1rn−/−) mice develop spontaneous polyarthritis that mimics human rheumatoid arthritis. We investigated whether a Toll-like receptor (TLR)/IL-1R signaling adaptor MyD88 and its downstream protein kinase D1 (PKD1) play a role in the development and progression of arthritis in IL-1rn−/− mice. Serum cytokine levels, and macrophage accumulation, matrix metalloproteinase activities and cartilage damage in joints were significantly lowered in MyD88−/−IL-1rn−/− mice compared to MyD88+/+ IL-1rn−/− mice. Development of arthritis was completely inhibited in MyD88−/− IL-1rn−/− mice, indicating an absolute requirement for MyD88 in the development of arthritis in IL-1rn−/− mice. Because PKD1 is essential for proinflammatory responses mediated by MyD88-dependent TLRs, we further investigated the contribution of PKD1 to the development of arthritis in IL-1rn−/− mice. Suppression of PKD1 expression in vitro 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, deletion of the PKD1 gene in IL-1rn−/− mice using a tamoxifen-inducible system significantly delayed development of arthritis and reduced the incidence and severity of arthritis in IL-1rn−/− mice. Our findings demonstrated that MyD88 and PKD1 are necessary for development of arthritis in IL-1rn−/− mice. This also implies that PKD1 might be one of the key factors that modulate proinflammatory responses in rheumatoid arthritis, and may serve as a therapeutic target.