Fibroblast-like synoviocytes shape inflammation and wound healing in Lyme arthritis

Abstract

Abstract Lyme arthritis (LA) is caused by infection with Borrelia burgdorferi (Bb) and, in many patients, can trigger autoimmune and autoinflammatory pathways. Despite proper treatment, some individuals can develop proliferative synovitis that persists for months or years, a condition known as post-infectious LA. Fibroblast-like synoviocytes (FLS) are the most abundant cell type found in the synovial lesion and are critical in wound healing. The aim of this study is to determine the role of FLS in dysregulated pro-inflammatory and tissue repair pathways in LA. FLS were cultured from joints of C57BL/6 (B6) mice and B6 Il10−/− mice and stimulated with interferongamma (IFNγ) and/or Bb. Cell culture supernatants were used for multiplex cytokine analysis, and RNA was isolated from cells for gene expression analysis. FLS were also used in flow cytometry and color flow imaging to identify immune markers, and in cell migration and proliferation assays as a measure of wound healing. When treated with IFNγ, FLS developed an immune-like phenotype. These immune fibroblasts were hyper-responsive to Bb and produced high levels of inflammatory mediators. FLS were also capable of internalizing Bb and expressing MHC-II molecules, suggesting the ability to present Bb antigen. Moreover, B6 FLS treated with IFNγ and/or Bb displayed an impaired wound healing phenotype, whereas this phenotype was seen intrinsically in both treated and untreated Il10−/− FLS. Under pro-inflammatory conditions seen in joints of patients, FLS likely play a key role in numerous pathogenic pathways, most notably in driving inflammation and blocking appropriate repair of damaged tissue. Further studies will examine the epigenetic pathways in both murine and human synovial tissue.