Targeting the IL-6–Yap–Snail signalling axis in synovial fibroblasts ameliorates inflammatory arthritis

Abstract

ObjectiveWe aimed to understand the role of the transcriptional co-factor Yes-associated protein (Yap) in the molecular pathway underpinning the pathogenic transformation of synovial fibroblasts (SF) in rheumatoid arthritis (RA) to become invasive and cause joint destruction.MethodsSynovium from patients with RA and mice with antigen-induced arthritis (AIA) was analysed by immunostaining and qRT-PCR. SF were targeted using Pdgfrα-CreER and Gdf5-Cre mice, crossed with fluorescent reporters for cell tracing and Yap-flox mice for conditional Yap ablation. Fibroblast phenotypes were analysed by flow cytometry, and arthritis severity was assessed by histology. Yap activation was detected using Yap–Tead reporter cells and Yap–Snail interaction by proximity ligation assay. SF invasiveness was analysed using matrigel-coated transwells.ResultsYap, its binding partner Snail and downstream target connective tissue growth factor were upregulated in hyperplastic human RA and in mouse AIA synovium, with Yap detected in SF but not macrophages. Lineage tracing showed polyclonal expansion of Pdgfrα-expressing SF during AIA, with predominant expansion of the Gdf5-lineage SF subpopulation descending from the embryonic joint interzone. Gdf5-lineage SF showed increased expression of Yap and adopted an erosive phenotype (podoplanin+Thy-1 cell surface antigen−), invading cartilage and bone. Conditional ablation of Yap in Gdf5-lineage cells or Pdgfrα-expressing fibroblasts ameliorated AIA. Interleukin (IL)-6, but not tumour necrosis factor alpha (TNF-α) or IL-1β, Jak-dependently activated Yap and induced Yap–Snail interaction. SF invasiveness induced by IL-6 stimulation or Snail overexpression was prevented by Yap knockdown, showing a critical role for Yap in SF transformation in RA.ConclusionsOur findings uncover the IL-6–Yap–Snail signalling axis in pathogenic SF in inflammatory arthritis.

YAP promotes cell-autonomous immune responses to tackle intracellularStaphylococcus aureus in vitro

“…In this model of synovial organoids, FLS forms a lining layer at the edge of the organoid, and more sparse cells in the core of the structure are organized like a stroma mimicking the human synovial membrane 36 ( Figure 7B ). Synovial lining layer thickening, which is recognized as a hallmark of synovial inflammation, was found to be mediated through YAP activity 36, 49, 50 . At 7 hpi, ST80 Δ edin B induced synovial lining layer thickening ( Figure 7B-D ) which suggest that YAP is activated.…”

YAP promotes cell-autonomous immune responses to tackle intracellular Staphylococcus aureus in vitro

“…7B ). Synovial lining layer thickening, which is recognized as a hallmark of synovial inflammation, was found to be mediated through YAP activity 36 , 50 , 51 . At 7 hpi, ST80 Δ edin B induced synovial lining layer thickening (Fig.…”

The Dynamic Feature of Macrophage M1/M2 Imbalance Facilitates the Progression of Non-Traumatic Osteonecrosis of the Femoral Head

“…IL-6 has also been suggested as an essential cytokine in the pathogenesis of chronic inflammatory disease ( Grom et al, 2016 ). Otherwise, IL-6 may also promote IL-1β secretion by macrophages, synovial fibroblasts and other cells ( Fernando et al, 2014 ; Symons et al, 2021 ). Based on these considerations, we believe that IL-6 may contribute more than IL-1β to angiogenesis, fibrosis formation and bone resorption during the progression of NONFH.…”