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Table 1 Proposed roles of extracellular vesicles in rheumatoid arthritis

From: Extracellular vesicles in the pathogenesis of rheumatoid arthritis and osteoarthritis

Process Description
Antigen presentation and immune complex formation Present antigens for recognition by immune cells. Proteins such as DEK, vimentin, fibrin, fibronectin, fibrinogen, and AIM are present in the membrane. These become citrullinated and are thought to activate the innate and adaptive immune system, resulting in inflammation. Additionally these antibodies form to these complexes and deposit in the tissues, resulting in increased inflammation [27, 31, 35]
Inflammation Carry membrane-bound TNF-α, which causes inflammation. EVs stimulate production of TNF-α, IL-6, IL-8, and mPGES-1, further increasing inflammation. Platelet-derived EVs are found in patients with RA and increase inflammation in an IL-1 receptor-mediated mechanism. Presence of EV-based immune complexes causes increased inflammation. EVs can activate TLR4, which triggers anti-inflammatory genes. EVs carry ANXA1 which reduces inflammatory cytokines [24, 3638, 41, 43, 47]
Destruction of ECM Carry catabolic proteases such as MMPs, ADAMTS-5, Hexosaminidase D, and B-glucuronidase. This causes the breakdown of ECM, resulting in the destruction of cartilage and more inflammation. ANXA1 in EVs activates anabolic genes in chondrocytes [47, 5157]
Biomarker Differences in content of synovial fluid and plasma EVs can serve as a biomarker for disease. There has proven to be an increased concentration of EVs in plasma of people with RA. Additionally, the presence of citrullinated proteins in EV membrane is a potential biomarker that is specific to RA [27, 41, 58]
Delivery of miRNA Deliver miRNA to cells altering response to inflammation. Dendritic cells are known to secrete EVs with increased levels of miR-155 and miR-146a in response to inflammation [5865]
Therapeutic EVs derived from IL-10-treated dendritic cells have shown anti-inflammatory properties in patients with RA. EVs have also been created that can target the synovial membrane specifically. Demonstration that EVs have anti-inflammatory properties illustrates the possibility of mimicking that stimulation therapeutically [43, 47, 7981]
  1. AIM apoptosis inhibitor of the macrophage, ANXA1 annexin A1, DEK DNA-binding protein, ECM extracellular matrix, EV extracellular vesicle, miRNA microRNA, MMP matrix metalloproteinase, mPGES-1 microsomal prostaglandin E synthase 1, RA rheumatoid arthritis, TLR4 Toll-like receptor 4