Impact of Mast cells on synovial inflammation and bone destruction in autoimmune-induced arthritis

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Mast cells (MCs) play a critical role in innate immunity and in the induction of adaptive immune responses. Increasing evidence suggests that MCs also have an important impact on the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA). The inflamed synovial tissue of RA-patients is characterized by a massive accumulation of MCs which correlates with the intensity of the joint inflammation. Furthermore, the intensified osteoclast differentiation as a hallmark of arthritis-induced bone destruction is modulated by proinflammatory mediators including RANKL, TNF, IL-1, IL-6 and IFN-g, all of which are known to be produced and secreted by MCs. This proposal addresses the role of MCs in synovial inflammation as well as cartilage and bone destruction. For this purpose, we will study the model of K/BxN serum transfer-induced arthritis in vivo in transgenic mice characterized by a selective depletion of MCs or by MC-specific inactivation of genes encoding cytokines or growth factors. Moreover, we will assess the capability of MCs to induce or modulate osteoclast differentiation in vitro and in vivo. Finally, we will establish a technique to visualize cellular interactions of MCs with joint infiltrating neutrophils or T cells directly in the inflamed joint by intravital 2-Photon-Microscopy. Understanding the mast celldriven effects on the arthritis-induced synovial inflammation and bone destruction may be of great importance to identify new targets for therapeutic strategies.