Polystyrene microplastics activate NF-κB/MAPK signaling in synovial fibroblasts, promoting inflammation and joint destruction in rheumatoid arthritis

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Microplastics (MPs) are emerging environmental contaminants, yet their impact on autoimmune diseases such as rheumatoid arthritis (RA) remains unclear. We report that polystyrene microplastics (PS-MPs) are detectable in synovial fluid samples from RA patients and that exposure to 5 μm PS-MPs directly promotes the pathogenic activation of RA fibroblast-like synoviocytes (RA-FLSs), key effector cells in synovial inflammation and joint destruction. High-resolution imaging confirmed PS-MPs internalization into the cytoplasm of RA-FLSs, accompanied by cytoskeletal changes and mitochondrial cristae disruption indicative of intracellular stress. PS-MPs exposure activated NF-κB and MAPK (JNK/p38) signaling and induced the expression of IL-6, IL-8, CCL2, MMP3, MMP9, NAMPT, and TWIST1. These changes coincided with enhanced migration, invasion, and monocyte adhesion via increased VCAM-1 and ICAM-1. In vivo , chronic PS-MPs exposure aggravated inflammation in CFA-induced arthritis, with fluorescent particles accumulating in inflamed synovium. In humanized SCID co-implantation model, PS-MPs–treated RA-FLSs triggered greater cartilage erosion and macrophage infiltration. Importantly, pharmacologic inhibition of NF-κB and p38, as well as treatment with Ginsenoside Compound K (GCK), significantly reduced PS-MPs–induced cytokine production in vitro . Together, these findings demonstrate that MPs can directly activate synovial fibroblasts and aggravate RA pathology. This study identifies MPs as a previously unrecognized environmental cofactor in autoimmune joint disease. • Polystyrene microplastics are detected in RA patient synovial fluid and activate synovial fibroblasts. • PS-MPs trigger NF-κB/MAPK signaling, promoting cytokine production and invasive RA-FLS behavior. • In vivo , PS-MPs aggravate joint inflammation and cartilage erosion in both CFA and humanized SCID arthritis models.

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