Review: Extracellular Vesicles in Joint Inflammation

The pathologic mechanisms underlying the development and maintenance of rheumatoid arthritis (RA) are incompletely understood but broadly involve persistent joint inflammation that can lead to irreversible joint damage. In recent years, extracellular vesicles (EVs) have attracted increasing attention for potential roles in inflammation, including in inflammatory arthritis (1). EVs are released from cells and are found in all types of bodily fluids. They are typically classified as exosomes, microvesicles, or apoptotic bodies, according to the mode of biogenesis (Figure 1). Exosomes and microvesicles are continually released from cells, whereas apoptotic bodies are released only when cells undergo apoptosis. The majority of research investigating EVs has been on exosomes and microvesicles, and these will be the focus of this review. EV nomenclature tends to be inconsistent within the literature, since it is technically difficult to isolate specific classes of EVs, leading to methodologic variability and a lack of consensus on not only optimal isolation techniques, but also what types of EVs are enriched (2). To ensure consistency within this review, we have therefore reviewed the isolation techniques within each study and adopted a consistent nomenclature. If a technique does not convincingly enrich for a particular class of EV, the general term EV is used. EVs contain a heterogeneous collection of proteins, RNAs and lipids, which reflect the state of the particular cells from which EVs are derived. Interactions between EVs and other cells can occur in several ways (Figure 2), enabling the molecular cargo of an EV to exert functional effects on recipient cells. It is clear that EVs can deliver molecules that drive disease. For example, EVs have been implicated in neurodegenerative disease through traffic of infectious, prion-like proteins (for review, see ref. 3), and in cancer through the transfer of oncoproteins to promote metastasis (4). EVs can also functionally impact recipient cells though the transfer of RNAs, such as microRNAs (miRNAs), which can influence the expression of target genes, including those involved in inflammatory processes (5,6). In the context of inflammation, EVs have been shown to exert both proand antiinflammatory effects. For example, exosomes from heat-stressed hepatocytes potently stimulate tumor necrosis factor (TNF) expression in recipient macrophages via exosome-associated Hsp70 (7). Similarly, EVs from neuronal stem/precursor cells exposed to Th1 cytokines can activate STAT-1 signaling via the delivery of EV-bound interferon-g (IFNg) to its cognate receptor on recipient cells (8). Moreover, exosomes purified from human amniotic fluid or malignant ascites fluid can promote STAT-3 and NF-kB signaling in recipient monocytes, through activation of the Tolllike receptors (TLRs) TLR-2 and TLR-4, leading to the release of cytokines such as TNF, interleukin-1b (IL-1b), and IL-6 (9). Similarly, exosomes derived from tumor cells contain specific miRNAs that act as agonists for endosomal TLRs in recipient immune cells (10). In contrast, some EVs have antiinflammatory effects. Suppressor of cytokine signaling (SOCS) family proteins are key suppressors of inflammation through inhibition of JAK/ STAT signaling (11). Exosomes and microvesicles isolated from alveolar macrophages contain SOCS-1 and SOCS-3, respectively, both of which can attenuate STAT signaling Supported by the National Health and Medical Research Council (grant 1064591) and the Reid Family Trust. Andrew D. Foers, BSc (Hons), Ian P. Wicks, MBBS, FRACP, PhD: The Walter & Eliza Hall Institute of Medical Research and The University of Melbourne, Parkville, Victoria, Australia; Lesley Cheng, BMsc (Hons), PhD, Andrew F. Hill, BSc (Hons), DIC, PhD: Latrobe University, Bundoora, Victoria, Australia; Ken C. Pang, MBBS (Hons), BMedSc, PhD, FRACP: Murdoch Childrens Research Institute and The University of Melbourne, Parkville, Victoria, Australia. Address correspondence to Ian P. Wicks, MBBS, FRACP, PhD, The Walter & Eliza Hall Institute, Parkville, Victoria 3052, Australia (e-mail: wicks@wehi.edu.au); or to Ken C. Pang, MBBS (Hons), BMedSc, PhD, FRACP, Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia (e-mail: ken.pang@mcri.edu.au). Submitted for publication November 14, 2016; accepted in revised form February 14, 2017.