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

肥大细胞（MC）在先天免疫和诱导适应性免疫应答中起关键作用。越来越多的证据表明，MCs也对包括类风湿性关节炎（RA）在内的自身免疫性疾病的发病机制有重要影响。RA患者发炎的滑膜组织的特征在于MC的大量积累，其与关节炎症的强度相关。此外，作为关节炎诱导的骨破坏的标志的破骨细胞分化的增强受到促炎介质的调节，所述促炎介质包括RANKL、TNF、IL-1、IL-6和IFN-g，所有这些都已知由MC产生和分泌。该提案解决了MC在滑膜炎症以及软骨和骨破坏中的作用。为了这个目的，我们将在转基因小鼠体内研究K/BxN血清转移诱导的关节炎模型，其特征在于选择性消耗MC或MC特异性失活编码细胞因子或生长因子的基因。此外，我们将评估MC在体外和体内诱导或调节破骨细胞分化的能力。最后，我们将建立一种技术，通过活体双光子显微镜直接在发炎关节中可视化MC与关节浸润中性粒细胞或T细胞的细胞相互作用。了解肥大细胞驱动的关节炎诱导的滑膜炎症和骨破坏的影响可能是非常重要的，以确定新的治疗策略的目标。

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.