Update on the role of extracellular vesicles in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a heterogeneous autoimmune disorder that leads to severe joint deformities, negatively affecting the patient's quality of life. Extracellular vesicles (EVs), which include exosomes and ectosomes, act as intercellular communication mediators in several physiological and pathological processes in various diseases including RA. In contrast, EVs secreted by mesenchymal stem cells perform an immunomodulatory function and stimulate cartilage repair, showing promising therapeutic results in animal models of RA. EVs from other sources, including dendritic cells, neutrophils and myeloid-derived suppressor cells, also influence the biological function of immune and joint cells. This review describes the role of EVs in the pathogenesis of RA and presents evidence supporting future studies on the therapeutic potential of EVs from different sources. This information will contribute to a better understanding of RA development, as well as a starting point for exploring cell-free-based therapies for RA.

Keywords: Exosomes; extracellular vesicles; immunomodulation; mesenchymal stem cell-derived extracellular vesicles; rheumatoid arthritis.

Fig. 1.

EVs from different sources of mesenchymal stem cells and their biogenesis pathways. The biogenesis of EVs (including exosomes and ectosomes) from different sources of MSCs follows a general process of EV production. Generally, ectosomes derive from direct budding from the plasma membrane, whereas exosomes result from two invaginations of the plasma membrane. EVs arrive at recipient cells and elicit functional responses via cellular uptake. EVs contain abundant cargoes (including DNAs, RNAs, proteins, lipids, etc.). Several surface molecules such as CD9, CD81 and CD63 can help to identify the origins of EVs from MSCs. ALIX, apoptosis-linked gene 2-interacting protein X; AMSC-EVs, adipose tissue mesenchymal stem cell-derived extracellular vesicles; BMSC-EVs, bone marrow mesenchymal stem cell-derived extracellular vesicles; ESCRT, endosomal sorting complexes required for transport; EVs, extracellular vesicles; HSP70, heat shock protein 70; MHC, major histocompatibility complex; MSC-EVs, mesenchymal stem cells; OE-MSC-EVs, olfactory ecto-mesenchymal stem cell-derived extracellular vesicles; TSG101, tumour susceptibility gene 101; UCMSC-EVs, umbilical cord mesenchymal stem cell-derived extracellular vesicles.

Fig. 2.

Schematic view of the potential mechanisms of mesenchymal stem cells-derived EVs in the treatments of rodent models of RA. EVs from different sources of MSCs show efficacy in the treatment of RA models. These EVs mainly show the immunosuppressive function of inhibiting T cell proliferation, downregulating Ig production and decreasing pro-inflammatory factors levels in vivo, thus attenuating clinical signs of paw swelling as well as histopathological indicators of bone and cartilage erosion and pannus formation. Several contents (including miR-34, TGF-β1 and IL-1ra) have been indicated to be associated with these functions. AMSC-EVs, adipose tissue mesenchymal stem cell-derived extracellular vesicles; BMSC-EVs, bone marrow mesenchymal stem cell-derived extracellular vesicles; CKs, cytokines; FLS, fibroblast-like synovial cells; FOXP3: forkhead box protein P3; Ig, immunoglobulin; IL, interleukin; IL-1ra, IL-1 receptor antagonist; miR-34, microRNA-34; MSC-EVs, mesenchymal stem cell-derived extracellular vesicles; PGE2, prostaglandin E2; RA, rheumatoid arthritis; ROR-γ, retinoic acid receptor-related orphan receptor γ; TGF-β: tumour growth factor beta; Th17, T helper 17; TNF-α, tumour necrosis factor alpha; Treg, regulatory T cells; Tr1, T regulatory type-1; UCMSC-EVs, umbilical cord mesenchymal stem cell-derived extracellular vesicles.