Identification of a transitional fibroblast function in very early rheumatoid arthritis

Abstract

ObjectivesSynovial fibroblasts actively regulate the inflammatory infiltrate by communicating with neighbouring endothelial cells (EC). Surprisingly, little is known about how the development of rheumatoid arthritis (RA) alters these immunomodulatory properties. We examined the effects of phase of RA and disease outcome (resolving vs persistence) on fibroblast crosstalk with EC and regulation of lymphocyte recruitment.MethodsFibroblasts were isolated from patients without synovitis, with resolving arthritis, very early RA (VeRA; symptom ≤12 weeks) and established RA undergoing joint replacement (JRep) surgery. Endothelial-fibroblast cocultures were formed on opposite sides of porous filters. Lymphocyte adhesion from flow, secretion of soluble mediators and interleukin 6 (IL-6) signalling were assessed.ResultsFibroblasts from non-inflamed and resolving arthritis were immunosuppressive, inhibiting lymphocyte recruitment to cytokine-treated endothelium. This effect was lost very early in the development of RA, such that fibroblasts no longer suppressed recruitment. Changes in IL-6 and transforming growth factor beta 1 (TGF-β1) signalling appeared critical for the loss of the immunosuppressive phenotype. In the absence of exogenous cytokines, JRep, but not VeRA, fibroblasts activated endothelium to support lymphocyte.ConclusionsIn RA, fibroblasts undergo two distinct changes in function: first a loss of immunosuppressive responses early in disease development, followed by the later acquisition of a stimulatory phenotype. Fibroblasts exhibit a transitional functional phenotype during the first 3 months of symptoms that contributes to the accumulation of persistent infiltrates. Finally, the role of IL-6 and TGF-β1 changes from immunosuppressive in resolving arthritis to stimulatory very early in the development of RA. Early interventions targeting ‘pathogenic’ fibroblasts may be required in order to restore protective regulatory processes.

Responses to Cytokine Inhibitors Associated with Cellular Composition in Models of Immune‐Mediated Inflammatory Arthritis

“…This is a simplistic model of inflammatory osteoclastogenesis without the addition of macrophage colony-stimulating factor or receptor activator of nuclear factor kappa-Β ligand (22). These findings are supported by a recent study showing that IL-6 is central for the transformation of FLSs in early RA from an immunosuppressive to an inflammatory phenotype (40). This is in line with the finding that anti-TNFα treatment reduces erosive joint damage in RA (15) even though the literature on this matter is contradictory.…”

Transcriptional Profiling of Synovial Macrophages Using Minimally Invasive Ultrasound‐Guided Synovial Biopsies in Rheumatoid Arthritis

“…Furthermore, these biopsies do not appear to alter subsequent clinical or ultrasound disease activity assessments, which is important for patients who might subsequently enroll in clinical trials (73). These European groups have also performed numerous studies to validate the needle biopsy and portal and forceps procedures and tissue sampling (34–36, 38–40, 67, 74, 75). Our data demonstrate that the ultrasound-guided synovial tissue biopsies obtained from patients with RA are sufficient for RNA-seq, distinguish differences between patients with RA and OA, and importantly sets the framework for the stratification of patients with RA according to the most prominent disease pathway.…”

Review: The Tumor‐Like Phenotype of Rheumatoid Synovium: Molecular Profiling and Prospects for Precision Medicine

“…Rheumatoid FLS exhibit unique pathologic characteristics that include 1) secretion of proinflammatory cytokines, prostanoids, and proangiogenic factors (7,(38)(39)(40), 2) enhanced proliferation and survival, and 3) invasive character via the expression of MMPs and adhesion molecules that bind extracellular components such as integrins and CD44 (41)(42)(43)(44)(45). These features are cell intrinsic, and their persistence in isolated cell culture has prompted a search for causative epigenetic modifications ( Figure 2).…”