Rheumatoid synovial fibroblasts differentiate into distinct subsets in the presence of cytokines and cartilage

Abstract

BackgroundWe investigated two distinct synovial fibroblast populations that were located preferentially in the lining or sub-lining layers and defined by their expression of either podoplanin (PDPN) or CD248, and explored their ability to undergo self-assembly and transmigration in vivo.MethodsSynovial fibroblasts (SF) were cultured in vitro and phenotypic changes following stimulation with interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β1 were examined. To examine the phenotype of SF in vivo, a severe combined immunodeficiency (SCID) human-mouse model of cartilage destruction was utilised.ResultsSF in the lining layer in rheumatoid arthritis (RA) expressed high levels of PDPN compared to the normal synovium, whereas CD248 expression was restricted to sub-lining layer cells. TNF-α or IL1 stimulation in vitro resulted in an increased expression of PDPN. In contrast, stimulation with TGF-β1 induced CD248 expression. In the SCID human-mouse model, rheumatoid SF recapitulated the expression of PDPN and CD248. Fibroblasts adjacent to cartilage expressed PDPN, and attached to, invaded, and degraded cartilage. PDPN+ CD248– SF preceded the appearance of PDPN– CD248+ cells in contralateral implants.ConclusionsWe have identified two distinct SF populations identified by expression of either PDPN or CD248 which are located within different anatomical compartments of the inflamed synovial membrane. These markers discriminate between SF subsets with distinct biological properties. As PDPN-expressing cells are associated with early fibroblast migration and cartilage erosion in vivo, we propose that PDPN-expressing cells may be an attractive therapeutic target in RA.

Tetraspanin CD82 affects migration, attachment and invasion of rheumatoid arthritis synovial fibroblasts

“…Potentially, at sites of inflammation and matrix destruction CD82-induction takes place, contributing to RASF accumulation. A similar observation has been made for podoplanin (PDPN) and CD248 with a high expression of PDPN in the LL, whereas CD248 expression was restricted to sublining cells 41. In this study, TNF or IL-1β also increased PDPN expression whereas TGF-ß induced CD248.…”

Immunopathogenesis of Rheumatoid Arthritis

“…In addition, activated FLS can play an active role in antigen presentation and contribute to local adaptive immune responses (Tran et al 2007). Finally, the synovial fibroblasts are not a uniform population but segregate into different phenotypes based, in part, on their cytokine profiles (Croft et al, 2016). The role of mesenchymal cells in disease initiation and progression represents an interesting therapeutic opportunity because no approved agents currently target these cells (see Figure 1 for alternate models of contribution of stromal cells and autoimmunity in a notional hierarchy – note that these are not mutually exclusive).…”

Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis

“…Indeed, it has now become apparent that there are subsets of synovial fibroblasts within the inflamed joint that display pro-and antiinflammatory phenotypes, with effects also dependent upon positional memory [83][84][85]. Indeed, it has now become apparent that there are subsets of synovial fibroblasts within the inflamed joint that display pro-and antiinflammatory phenotypes, with effects also dependent upon positional memory [83][84][85].…”