Apurinic/apyrimidinic endonuclease 1 alleviates inflammation in fibroblast-like synoviocytes from patients with rheumatoid arthritis

Introduction: Apurinic/apyrimidinic endonuclease 1 (APEX1) is a protein with elevated expression in synovial fluids from rheumatoid arthritis (RA) patients. However, its role in RA pathogenesis remains unexplored. This study investigated the influence of APEX1 on inflammatory pathways in fibroblast-like synoviocytes (FLS) isolated from RA patients. Material and methods: FLS from RA patients (n = 5) were stimulated with recombinant tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-17. Subsequently, cells were treated with recombinant APEX1, and assessments were made on reactive oxygen species (ROS) production and mitochondrial membrane potential. Additionally, mRNA levels of IL-1 family members were quantified. Cell migration was evaluated through Transwell chamber assays, and levels of key secreted inflammatory cytokines were measured via enzyme-linked immunosorbent assay (ELISA). Results: The results demonstrated that APEX1 significantly reduced mitochondrial-specific ROS expression and restored mitochondrial membrane potential in TNF-alpha/IL-17-stimulated RA FLS. Furthermore, APEX1 treatments attenuated TNF-alpha/IL-17-induced activation of p38 MAPK, NF-kappa B, and PI3K 110 delta signaling pathways. Similarly, APEX1 significantly diminished TNF-alpha/IL-17-induced expression of inflammatory cytokines, including IL-1 family members, IL-6, IL-8, and vascular endothelial via inhibition of matrix metalloproteinase 3 (MMP3). Conclusions: These findings collectively underscore the role of APEX1 as a key mediator of cytokine-amplified migration, modulating ROS and MMP3 in RA FLS, thus supporting its potential as a therapeutic target in RA treatment.