Cadherin 11 Regulates Synovial Inflammation in Arthritis

描述(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，表达在滑膜成纤维细胞上的亲水性细胞黏附分子钙粘蛋白-11(cad-11)介导了它们的黏附，形成了滑膜衬里和滑膜下层基质网络的结构。在类风湿性关节炎中，衬里层经历了大量的增殖和激活，并产生了降解软骨的血管疙瘩。滑膜下层慢性渗入白细胞(T和B细胞、巨噬细胞、肥大细胞)。我们推测，对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，组织基质网络及其产物可能由表达钙粘素-11的成纤维细胞提供。我们最近的工作表明，将cad-11靶向滑膜成纤维细胞不仅改变了滑膜结构，而且显著地消除了小鼠关节炎模型中的炎症。此外，我们还发现，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，从而产生了多种已知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，它们可以通过它们表达的间充质钙粘素-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，我们将确定人类滑膜成纤维细胞亚群在基础条件下以及在炎性细胞因子刺激后产生的关键细胞因子和趋化因子，这些细胞因子和趋化因子与RA中发现的炎性细胞因子刺激相对应(目标1)。第二，我们将在2D和3D器官培养中确定cad-11在调节巨噬细胞的激活和炎症表型中的作用(目标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-1ç产生中的作用(目标3)。最后，为了确定成纤维细胞对巨噬细胞炎症表型的调控和上述在体外定义的人类细胞中的Th17分化是否也与体内相关，我们将确定靶向cad-11如何改变胶原性关节炎(CIA)小鼠的巨噬细胞和T细胞表型(目标4)。总之，这些研究将为针对关节炎间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.