Small matters: Introduction to extracellular vesicles

This special issue of Immunological Reviews is devoted to extracellular vesicles (EVs), which comprise microvesicles (also known as microparticles), exosomes, ectosomes, and elongated neutrophil-derived structures (ENDS). Six leading research groups provide their perspective in six reviews, providing different perspectives, opinions, and areas of focus. The EV field is now mature, moving from the realm of basic research into translation for diagnostic and therapeutic purposes. Lina Badimon of San Pau, Barcelona, Spain, and her group focus on the promise that EVs hold as prognostic, diagnostic, and predictive markers of atherosclerotic cardiovascular disease (ASCVD). Acute events from ASCVD are triggered by arterial atherothrombosis, in which EVs play important roles in the initiation, progression, and complications of atherosclerosis. EVs come from all cells. Some have been shown to be predictive, others prognostic, and some diagnostic of manifest disease. Perhaps best understood are platelet-derived EVs, which are clearly prothrombotic, but EVs can also be involved in neovascularization and angiogenesis, suggesting therapeutic potential.1 Elena Aikawa of Harvard Medical School, Boston, USA, writes on extracellular vesicle-mediated cardiovascular calcification. EVs are derived from various cell types and can become calcifying. These calcifying EVs initiate microcalcifications, which can progress to the macrocalcification lesions that are visualized clinically. The authors stress the importance of future work that will link inflammation and calcification. It is likely that EVs have a mechanistic role in promoting calcifications.2 Eric Boilard and Marie Bellio of the Université Laval, Quebec, Canada, focus on platelet EVs. Since EVs are released by cells under various conditions and are found in the extracellular milieu in all biological fluids, the assessment of EVs can be used as a proxy for cellular activation.3 EVs contain cytokines, growth factors, organelles (mitochondria and proteasomes), RNA, transcription factors, and autoantigens. The surface of platelet EVs is studded with P-selectin, CLEC-2, gpIIb/IIIa, and MHC class I. Platelet EVs produce 12-S-HETE, which can activate neutrophils through BLTR2. In autoimmune diseases, EVs are associated with autoantibodies. Secreted phospholipases abundantly expressed in the extracellular milieu can break down the EV's phospholipid shell. Circulating EVs may contribute to immunity through the activity of their cargo or by interacting with serum proteins. Alex Marki and Klaus Ley from the La Jolla Institute of Immunology in La Jolla, CA, USA, focus on neutrophil-derived EVs. Neutrophils make exosomes and ectosomes, migratory cytoplasts, migrasomes, and elongated neutrophil-derived structures (ENDS). ENDS are the newest addition to the family. ENDS form by tether detachment from rolling neutrophils. They are elongated, about 7 μm long and 115 nm thick. Their function remains unknown.4 Nigel Mackman and colleagues from the University of North Carolina at Chapel Hill, NC, USA, write on circulating tissue factor-positive (TF+) extracellular vesicles and thrombosis. These EVs are important in human immunodeficiency virus (HIV), influenza A virus (IAV), and severe acute respiratory syndrome caused by SARS-CoV-2. Monocytes are the major sources of TF + EVs in blood, but alveolar epithelial cells are the major source of TF + EVs in bronchoalveolar lavage fluid of SARS-CoV-2 and influenza A patients. The authors suggest that TF + EVs could be used as a biomarker to identify patients that have an increased risk of coagulopathy and mortality.5 A more applied view on EVs comes from Ali Arbab and colleagues of Augusta University, Augusta, GA, USA. The authors review “designer” exosomes and engineered exosomes that can carry biologically active protein on the surface and drugs, microRNA, and other products to the site of interest, like a tumor or its metastases. This article also reviews how engineered exosomes affect immune-inflammatory responses and their potential in various diseases. The authors discuss targeting by transmembrane proteins, GPI-anchored proteins, phospholipid-anchored cargo, and chemically and biologically modified proteins. They also discuss how exosomes can be made resistant to phagocytosis by using CD47 as a “don't eat-me” signal and other mechanisms.6 Altogether, the six contributions review a large number of studies regarding EV release, content, and their potential local or remote biological effects. Understanding the role of EVs in tissue homeostasis and disease development requires some caution as few studies have addressed these questions in vivo. Furthermore, we need to keep in mind that EVs are one of the many mediators, in addition to cytokines, chemokines, enzymes, and others that cells can release. The beautiful complexity of the cellular secretome remains a challenge for years to come. Interesting opportunities to tame EVs arise from several studies engineering vesicles for therapeutic purposes; there is little doubt that these approaches will be opening new avenues for research. No conflicts of interest to declare.