Extracellular vesicle-mediated immune crosstalk in rheumatoid arthritis synovium: mechanistic insights and translational challenges
TL;DR
This mini-review examines EV biogenesis, movement across the synovial barrier, and uptake by recipient cells in RA and evaluates evidence linking EV cargo to NF-κB, MAPK, JAK-STAT, and cGAS-STING signaling; innate and adaptive immune activation; fibroblast-like synoviocyte invasion; and osteoclast differentiation.
Abstract
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease marked by persistent synovial inflammation, autoantibody production, cartilage damage, and bone erosion. Biologic disease-modifying antirheumatic drugs (DMARDs) and targeted small-molecule therapies have improved disease control, but durable remission remains difficult for many patients. Low-grade synovitis and structural damage may continue despite treatment. Extracellular vesicles (EVs) may contribute to this residual activity by carrying signals that are not captured by soluble cytokine measurements alone. In the inflamed joint, EVs are released by fibroblast-like synoviocytes, macrophages, neutrophils, endothelial cells, chondrocytes, and osteoclast precursors. Their cargo includes citrullinated proteins, inflammatory mediators, miRNAs, lipids, and matrix-degrading enzymes and often reflects the state of the parent cell. This mini-review examines EV biogenesis, movement across the synovial barrier, and uptake by recipient cells in RA. It evaluates evidence linking EV cargo to NF-κB, MAPK, JAK-STAT, and cGAS-STING signaling; innate and adaptive immune activation; fibroblast-like synoviocyte invasion; and osteoclast differentiation. We also assess the current evidence for EVs as biomarkers and therapeutic vehicles, with particular attention to methodological and translational limitations.