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，在滑膜成纤维细胞上表达的亲同质细胞粘附分子钙粘蛋白-11 （cadherin-11, cad-11）介导滑膜成纤维细胞的粘附，形成滑膜衬里的结构和下层滑膜的基质网络。在类风湿性关节炎中，衬里层经历大量增生和活化，并产生使软骨降解的泛膜。滑膜下层逐渐浸润白细胞（T细胞、B细胞、巨噬细胞、肥大细胞）。我们假设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，而滑膜中的基质网络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，将cad-11靶向滑膜成纤维细胞不仅能改变滑膜结构，还能显著消除小鼠关节炎模型中的炎症。此外，我们发现，在成纤维细胞表面的选择性cad-11激活了它们的MAP激酶和NF-κB通路，从而引发了各种已知的促进炎症的细胞因子和趋化因子。因此，滑膜成纤维细胞影响炎症，它们可以通过其表达的间充质钙粘蛋白-11在动物模型中被靶向。在这里，我们提出确定滑膜成纤维细胞和cad-11调节与RA相关的巨噬细胞和Th17细胞的机制。首先，我们将定义在体外基础条件下，以及在RA中发现的炎症细胞因子刺激下，人滑膜成纤维细胞亚群产生的关键细胞因子和趋化因子，这些细胞亚群对应于内层和下层成纤维细胞（Aim 1）。其次，我们将确定2D和3D器官培养中cad-11对成纤维细胞在调节巨噬细胞激活和炎症表型中的作用（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-1ß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症表型和上述人类细胞体外Th17分化的调节是否也与体内相关，我们将确定靶向cad-11如何改变小鼠胶原诱导关节炎（CIA）模型中的巨噬细胞和T细胞表型（Aim 4）。总之，这些研究将为关节炎间质成纤维细胞和炎症的机制和潜在治疗提供重要的新见解。

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.