Contents lists available at ScienceDirect Cytokine and Growth Factor Reviews journal homepage: www.elsevier.com/locate/cytogfr An emerging interplay between extracellular vesicles and cytokines Alessandra Aiello 1 , Flavia Giannessi 1 , Zulema A. Percario, Eisabetta Affabris* Department of Sciences, University Roma Tre, Rome, Italy ARTICLEINFO Keywords: Extracellular vesicles Cytokines TNFα IL-1β IFN ABSTRACT Extracellular vesicles (EVs) are small membrane-bound particles that are naturally released from cells. They are recognized as potent vehicles of intercellular communication both in prokaryotes and eukaryotes. Because of their capacity to carry biological macromolecules such as proteins, lipids and nucleic acids, EVs influence dif- ferent physiological and pathological functions of both parental and recipient cells. Although multiple pathways have been proposed for cytokine secretion beyond the classical ER/Golgi route, EVs have recently recognized as an alternative secretory mechanism. Interestingly, cytokines/chemokines exploit these vesicles to be released into the extracellular milieu, and also appear to modulate their release, trafficking and/or content. In this re- view, we provide an overview of the cytokines/chemokines that are known to be associated with EVs or their regulation with a focus on TNFα, IL-1β and IFNs. 1. Introduction During the course of evolution, both prokaryotes and eukaryotes have developed cell-to-cell communication strategies that play a vital role in the systemic function of multicellular organisms. Classically, intercellular communication is mediated through direct cell-cell contact (juxtacrine signalling) and/or by secreting a diverse array of soluble factors such as hormones, growth factors, cytokines and chemokines. These soluble molecules can act both on the cell itself (autocrine sig- nalling) and on neighbouring (paracrine signalling) and distant cells (endocrine signalling). In the last two decades, transfer of extracellular vesicles (EVs) has emerged as a third mechanism of intercellular com- munication. EVs are heterogeneous membrane-enclosed structures re- leased by cells into the extracellular milieu in an evolutionally con- served manner, ranging from organisms such as prokaryotes to higher eukaryotes and plants. The first observation of EVs in the extracellular milieu dates back to the late 1940s when Chargaff and West observed EVs as procoagulant platelet-derived particles in normal plasma [1]. Since then, EVs have been isolated from most cell types and biolo- gical fluids, including blood, urine, saliva, breast milk, amniotic fluid, ascites, cerebrospinal fluid, bile and semen [2–7]. The accumulating data have indicated that these vesicles have different origin, size and composition and, based on their biogenesis, have been divided in three main subgroups: microvesicles, exosomes and apoptotic bodies [8] (see Fig.1). Although the nomenclature is still a matter of debate because there is not a standard method of isolation and analysis of the EVs [9, 10], the term microvesicle generally refers to vesicles (150−1000 nm) that bud directly from the plasma membrane. Before their shedding, cytoplasmic protrusions are generated by the cell, which undergoes fission events, finally resulting in the budding of microvesicles from the cellular membrane [11]. Although microvesicles can be generated by resting cells, stimulating events, leading to increased intracellular cal- cium levels, result in cellular membrane remodelling and enhance mi- crovesicles secretion [12]. The term exosome refers to smaller vesicles (30−150 nm) that are generated intracellularly as intraluminal vesicles (ILVs) by inward invagination of endosome membranes, giving rise to multivesicular bodies (MVBs). These endosomal compartments then fuse with lysosomes for ILV degradation, or with the plasma membrane releasing the ILVs into the extracellular milieu where they are called exosomes (reviewed by ref [9,10]). This type of vesicle is the most in- vestigated class of EVs, and their name was first proposed in 1987 when Johnstone and colleagues observed by ultrastructural studies the https://doi.org/10.1016/j.cytogfr.2019.12.003 Received 20 November 2019; Received in revised form 17 December 2019; Accepted 17 December 2019 Abbreviations: EVs, extracellular vesicles; MVBs, multivesicular bodies; ILVs, intraluminal vesicles; ER, endoplasmic reticulum; DCs, dendritic cells; IFN, Interferon; ISG, interferon-stimulated genes; NK, Natural Killer; TLRs, Toll-like-receptors; LPS, lipopolysaccharide; UPS, unconventional protein secretion; ABC, ATP binding cassette; TNF, tumour necrosis factor; CD40L, CD40 ligand; FasL, Fas ligand; TRAIL, TNF-related apoptosis inducing ligand; TACE, TNFα converting enzyme; TEVs, tumor-derived EVs ⁎ Corresponding author at: Department of Sciences, Roma Tre University, Viale Guglielmo Marconi, Rome, Italy. E-mail addresses: alessandra.aiello@uniroma3.it (A. Aiello), flavia.giannessi@uniroma3.it (F. Giannessi), zulema.percario@uniroma3.it (Z.A. Percario), elisabetta.affabris@uniroma3.it (E. Affabris). 1 A.A. and F.G. equally contributed to the work. Cytokine and Growth Factor Reviews xxx (xxxx) xxx–xxx 1359-6101/ © 2019 Published by Elsevier Ltd. Please cite this article as: Alessandra Aiello, et al., Cytokine and Growth Factor Reviews, https://doi.org/10.1016/j.cytogfr.2019.12.003