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The role of macrophages extracellular traps on the biologic behaviors of FLSs from patients with RA

ABSTRACT: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammatory in joints. Macrophages are abundant in synovial tissue and fluid of RA. Macrophages extracellular traps (METs) are induced from macrophages and may generate a stable autoantigen-DNA complexes, leading to the generation of autoantibodies and development of autoimmunity. We aimed to investigate the role of METs on the biologic behaviors of FLSs from patients with RA. RA-FLS from 3 independent RA patients were treated with METs, and performed whole transcriptome sequencing on MET-treated and untreated groups in a total of 6 groups. Further, we performed bioinformatic analysis on the sequencing results (Novogene, China). The transcriptome was first explored for differentially expressed genes and the main results were visualized with a heatmap. Next, GO and KEGG enrichment analysis were performed on the differential genes. The results were visualized using dot plots to explore which functions of RA-FLS may be affected by MET and the potential pathways that affect RA-FLS function

ORGANISM(S): Homo sapiens

PROVIDER: GSE216181 | GEO | 2022/10/25

REPOSITORIES: GEO

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Project description:Inflammation-mediated oncogenesis has been implicated in a variety of cancer types. Rheumatoid synovial tissues can be viewed as a tumor-like mass, consisting of hyperplastic fibroblast-like synoviocytes (FLSs). FLSs of rheumatoid arthritis (RA) patients have pro-migratory and invasive characteristics, which may be caused by chronic exposure to genotoxic stimuli, including hypoxia and growth factors. We tested whether a transformed phenotype of RA-FLSs is associated with placental growth factor (PlGF), a representative angiogenic growth factor induced by hypoxia. Here, we identified PlGF-1 and PlGF-2 as the major PlGF isoforms in RA-FLSs. Global gene expression profiling revealed that cell proliferation, apoptosis, angiogenesis, and cell migration were mainly represented by differentially expressed genes in RA-FLSs transfected with siRNA for PlGF. Indeed, PlGF-deficient RA-FLSs showed a decrease in cell proliferation, migration, and invasion, but an increase in apoptotic death in vitro. PlGF gene overexpression resulted in the opposite effects. Moreover, exogeneous PlGF-1 and PlGF-2 increased survival, migration, and invasiveness of RA-FLSs by binding their receptors, Flt-1 and NP-1, up-regulating the expression of anti-apoptotic molecules, pErk and Bcl2. Knock-down of PlGF transcripts reduced RA-FLS proliferation in a xeno-transplantation model. Collectively, in addition to their role for neovascularization, PlGF-1 and -2 promote proliferation, survival, migration, and invasion of RA-FLSs in an autocrine and paracrine manner. These results demonstrated how primary cells of mesenchymal origin acquired an aggressive and transformed phenotype. PlGF and its receptors thus offer new targets for anti-FLS therapy. The FLSs were prepared from the synovial tissues of RA patients and incubated in DMEM supplemented with 10% FBS. Cells were cultured in RPMI supplemented with 10% FBS. There are 4 FLS samples treated with PlGF siRNA, and 4 FLS samples treated with control siRNA.

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The role of macrophages extracellular traps on the biologic behaviors of FLSs from patients with RA

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