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-?B 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-1 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.
Rheumatoid arthritis causes pain and swelling in the joints and attacks and damages the joint structures. We are determining what regulates the underlying inflammation in the joint. Working out the mechanisms that cause inflammation helps to explain what goes wrong in rheumatoid arthritis. We have found that special cells (called fibroblasts) form the structure of the membrane that lines joints, known as the synovium. These special cells form a bed (called the stroma) to which all the inflammatory white blood cells attach. By targeting these cells, we disrupt the comfortable bed that the inflammatory cells need to produce inflammation. The cells that make up the bed and the markers we have found they express offer new targets for treating inflammation in rheumatoid arthritis
|Mizoguchi, Fumitaka; Slowikowski, Kamil; Wei, Kevin et al. (2018) Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat Commun 9:789|
|Chang, Sook Kyung; Kohlgruber, Ayano C; Mizoguchi, Fumitaka et al. (2017) Stromal cell cadherin-11 regulates adipose tissue inflammation and diabetes. J Clin Invest 127:3300-3312|
|Nguyen, Hung N; Noss, Erika H; Mizoguchi, Fumitaka et al. (2017) Autocrine Loop Involving IL-6 Family Member LIF, LIF Receptor, and STAT4 Drives Sustained Fibroblast Production of Inflammatory Mediators. Immunity 46:220-232|