Cadherin 11 Regulates Synovial Inflammation in Arthritis

描述（由申请人提供）：类风湿性关节炎（RA）是一种滑膜慢性炎症性疾病。我们发现，钙粘蛋白-11（cad-11），一种在滑膜成纤维细胞上表达的同种细胞粘附分子，介导它们的粘附形成滑膜衬里和下层滑膜的基质网络的结构。在RA中，衬里层经历大量增生和活化，并产生使软骨降解的血管翳。滑膜下层被白细胞（T和B细胞、巨噬细胞、肥大细胞）慢性浸润。我们推测，这种白细胞浸润的长期支持可能依赖于组织基质网络及其产物，在滑膜中可能由表达钙粘蛋白-11的成纤维细胞提供。我们最近的研究表明，在小鼠关节炎模型中，将cad-11靶向于滑膜成纤维细胞不仅可以改变滑膜结构，而且可以显著消除炎症。此外，我们发现，选择性的cad-11在成纤维细胞表面的结合激活其MAP激酶和NF-κ B途径，以引发多种细胞因子和趋化因子，已知促进炎症。因此，滑膜成纤维细胞影响炎症，并且它们可以通过它们表达的间充质钙粘蛋白-11在动物模型中被靶向。在这里，我们建议定义滑膜成纤维细胞和cad-11调节与RA相关的巨噬细胞和Th17细胞的机制。首先，我们将定义关键的细胞因子和趋化因子的人滑膜成纤维细胞亚群对应的衬里和亚衬里成纤维细胞在基础条件下，在体外，他们被炎性细胞因子刺激后，发现在RA（目的1）。其次，我们将确定cad-11在2D和3D器官培养物中成纤维细胞上调节巨噬细胞活化和炎症表型的作用（目的2）。然后，我们将确定cad-11和滑膜成纤维细胞以及巨噬细胞在调节影响Th17细胞分化的IL-6和IL-1 β产生中的作用（目的3）。最后，为了确定成纤维细胞对巨噬细胞炎性表型的调节和上述体外人细胞中的Th17分化在体内是否也相关，我们将确定靶向cad-11如何改变小鼠胶原诱导的关节炎（CIA）模型中的巨噬细胞和T细胞表型（目的4）。总之，这些研究将为针对关节炎中基质成纤维细胞和炎症的机制和潜在疗法提供重要的新见解。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic inflammatory disease in the synovium. We found that cadherin-11 (cad-11), a homophilic cell adhesion molecule expressed on synovial fibroblasts, mediates their adhesion to form the architecture of the synovial lining and stromal network of the sublining synovium. In RA, the lining layer undergoes massive hyperplasia and activation and gives rise to the pannus that degrades the cartilage. The synovial sublining becomes chronically infiltrated with leukocytes (T and B cells, macrophages, mast cells). We hypothesize that longterm support for such leukocytic infiltrates may be dependent on the tissue stromal network and its products, which in the synovium may be provided by cadherin-11 expressing fibroblasts. Our recent work shows that targeting cad-11 on synovial fibroblasts not only alters synovial architecture, but also markedly abrogates inflammation in arthritis models in mice. Further, we found that selective cad-11 engagement on the surface of fibroblasts activates their MAP kinase and NF-κB pathways to elicit a variety of cytokines and chemokines known to promote inflammation. Thus, synovial fibroblasts influence inflammation, and they can be targeted in animal models via the mesenchymal cadherin-11 they express. Here, we propose to define the mechanisms by which synovial fibroblasts and cad-11 regulate macrophages and Th17 cells that are relevant to RA. First, we will define the key cytokines and chemokines made by human synovial fibroblast subsets corresponding to lining and sublining fibroblasts in vitro under basal conditions and after they are stimulated by inflammatory cytokines as are found in RA (Aim 1). Second, we will determine the role of cad-11 on fibroblasts in 2D and 3D organ cultures in modulating the activation and inflammatory phenotype of macrophages (Aim 2). Then, we will determine the role of cad-11 and the synovial fibroblasts together with macrophages in regulating IL-6 and IL-1ß production that impact Th17 cell differentiation (Aim 3). Finally, to determine if fibroblast regulation of macrophage inflammatory phenotype and Th17 differentiation defined above in vitro in human cells also are relevant in vivo, we will determine how targeting cad-11 alters macrophage and T cell phenotypes in the collagen-induced arthritis (CIA) model in mice (Aim 4). Together, these studies will provide important new insights into mechanisms and potential therapies aimed at stromal fibroblasts and inflammation in arthritis.