Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis

Abstract

ObjectivesSynovial fibroblasts (SFs) are one of the major components of the inflamed synovium in rheumatoid arthritis (RA). We aimed to gain insight into the pathogenic mechanisms of SFs through elucidating the genetic contribution to molecular regulatory networks under inflammatory condition.MethodsSFs from RA and osteoarthritis (OA) patients (n=30 each) were stimulated with eight different cytokines (interferon (IFN)-α, IFN-γ, tumour necrosis factor-α, interleukin (IL)-1β, IL-6/sIL-6R, IL-17, transforming growth factor-β1, IL-18) or a combination of all 8 (8-mix). Peripheral blood mononuclear cells were fractioned into five immune cell subsets (CD4+ T cells, CD8+ T cells, B cells, natural killer (NK) cells, monocytes). Integrative analyses including mRNA expression, histone modifications (H3K27ac, H3K4me1, H3K4me3), three-dimensional (3D) genome architecture and genetic variations of single nucleotide polymorphisms (SNPs) were performed.ResultsUnstimulated RASFs differed markedly from OASFs in the transcriptome and epigenome. Meanwhile, most of the responses to stimulations were shared between the diseases. Activated SFs expressed pathogenic genes, including CD40 whose induction by IFN-γ was significantly affected by an RA risk SNP (rs6074022). On chromatin remodelling in activated SFs, RA risk loci were enriched in clusters of enhancers (super-enhancers; SEs) induced by synergistic proinflammatory cytokines. An RA risk SNP (rs28411362), located in an SE under synergistically acting cytokines, formed 3D contact with the promoter of metal-regulatory transcription factor-1 (MTF1) gene, whose binding motif showed significant enrichment in stimulation specific-SEs. Consistently, inhibition of MTF1 suppressed cytokine and chemokine production from SFs and ameliorated mice model of arthritis.ConclusionsOur findings established the dynamic landscape of activated SFs and yielded potential therapeutic targets associated with genetic risk of RA.

Cationic Amino Acid Transporter-1 (CAT-1) Promotes Fibroblast-Like Synoviocytes Proliferation and Cytokine Secretion by Taking Up L-Arginine in Rheumatoid Arthritis

“…This may be because the abnormal proliferation of FLSs in RA requires a large amount of nutrients, and the high concentration of L-arginine promotes the proliferation of FLSs and the activation of immune cells: the amount of cytokines secreted by the increased FLSs increases, and the activation of immune cells also secretes many cytokines. Furthermore, previous studies have shown that in addition to IL-1β, IL-6, and IL-8, other cytokines, such as TNF-α and IFN-γ, are also elevated in RA articular uid [22][23][24][25], but in this study, there was no signi cant difference compared to the concentrations observed in OA synovial uid. This may be due to the small sample size (only 9 samples were used in this study), or perhaps different control samples should have been selected.…”

Dimethylamino group modified polydopamine nanoparticles with positive charges to scavenge cell-free DNA for rheumatoid arthritis therapy

“…Under microscope, RA was characterized by synovial inflammation and hyperplasia with pannus formation, causing bone and cartilage destruction [ 46 ]. In synovial tissues, lymphocytes and synoviocytes produced excessive inflammatory cytokines, such as IL-6, IL-1β and TNF-α, leading to synovitis [ 47 ]. Furthermore, cytokine stimulated synoviocytes secreted MMP and receptor activator of nuclear factor kappa B ligand (RANKL) into SF and consequently lead to cartilage degradation and joint destruction [ 48 ].…”

Kruppel-like factor 4 as a therapeutically tractable brake on lung fibroblast activation which promotes resolution of pulmonary fibrosis

“…APTO-253 was administered at 25 mg/kg i.p. (a dose based on that employed in a mouse model of arthritis 30 ) every other day beginning at day 9 post-bleomycin until day 19, and lungs were harvested on day 21 (Figure 6A). As previously shown with this same model in Figure 4, bleomycin administration resulted in severe alveolar obliteration (Figure 6B and Supplemental Figure 12) and a significant increase in lung hydroxyproline content (Figure 6C).…”