The distinct transcriptomic signature of the resolution phase fibroblast-like synoviocytes supports endothelial cell dysfunction

Patients suffering from rheumatoid arthritis (RA) and related autoimmune joint diseases exhibit cyclic episodes of resolution and exacerbation of joint inflammation, referred to as flares. Fibroblast-like synoviocytes (FLSs) that are epigenetically transformed by chronic inflammation are implicated as the orchestrators of these flares. In this study, we compared the cellular and molecular features of the FLSs during the inflammatory and resolution phases of RA progression. We performed histopathological evaluations of the joints from an inducible tumor necrosis factor-alpha (TNF-α) transgenic mouse model to reveal that phenotypic RA hallmarks including synovial hyperplasia, increased angiogenesis, and macrophage infiltration, were all reversed upon the initiation of resolution. However, the FLSs from the resolution phase joints exhibited a transcriptomic signature reminiscent of a highly inflammatory state. They exhibited a G0/G1 cell cycle arrest accompanied by reduced viability. In addition, factors secreted from the resolution FLSs, induced cell death, and decreased the angiogenic potential in human microvascular and umbilical cord endothelial cells. These findings indicate that the secretome of the resolution phase FLSs impairs endothelial cell function and suggest that understanding the interaction between the FLSs and endothelial cells during the resolution phase of RA is essential for achieving complete remission.