Impact of extracellular vesicles on innate immunity

Abstract

Purpose of review: Extracellular vesicles released by prokaryote or eukaryote cells are emerging as mechanisms of cell-to-cell communication, by either physically interacting with the surface of target cells or transferring proteins/peptides, lipids, carbohydrates, and nuclei acids to acceptor cells. Accumulating evidence indicates that extracellular vesicles, among other functions, regulate innate and adaptive immune responses. We revisit here the effects that extracellular vesicles of various origins have on innate immunity.

Recent findings: Extracellular vesicles comprise a heterogeneous group of vesicles with different biogenesis, composition and biological properties, which include exosomes, microvesicles, apoptotic cell-derived extracellular vesicles, and other extracellular vesicles still not well characterized. Extracellular vesicles released by pathogens, leukocytes, nonhematopoietic cells, tumor cells, and likely allografts, can either stimulate or suppress innate immunity via multiple mechanisms. These include transfer to target leukocytes of pro-inflammatory or anti-inflammatory mediators, membrane receptors, enzymes, mRNAs, and noncoding RNAs; and interaction of extracellular vesicles with the complement and coagulation systems. As a result, extracellular vesicles affect differentiation, polarization, activation, tissue recruitment, cytokine and chemokine production, cytolytic and phagocytic function, and antigen transfer ability, of different types of innate immune cells.

Summary: The field of intercellular communication via extracellular vesicles is a rapid evolving area and the effects of pathogen-derived and host-derived extracellular vesicles on innate immunity in particular, have received increasing attention during the past decade. Future studies will be necessary to assess the full potential of the crosstalk between extracellular vesicles and the innate immune system and its use for therapeutic applications to treat chronic inflammation-based diseases and cancer growth and dissemination, among the growing list of disorders in which the innate immune system plays a critical role.

Figure 1:. Biogenesis of EVs in living or dying eukaryotic cells.

A) Living cells generate different types of EVs via multiple mechanisms. Microvesicles (MVs) are released by shedding of the plasma membrane. Exosomes are generated as intraluminal vesicles (ILVs) by reverse budding of the limiting membrane of early endosomes. Late endosomes containing ILVs are termed multivesicular bodies (MVBs). By fusing with the plasma membrane, MVBs release their cargo of ILVs to the extracellular space or bodily fluids, where the ILVs are termed exosomes. Alternatively, MVBs fuse with autophagosomes, which may contain fragments of double stranded (ds) DNA, forming intracellular vesicles termed amphisomes, which also release their content of ILVs and dsDNA to the extracellular milieu. In the latter case, the dsDNA fragments released by exocytosis are not associated physically to the exosomes secreted simultaneously from the same amphisome. MVBs, autophagosomes, and amphisomes can alternatively merge with lysosomes where their vesicular content is degraded. B) Cells undergoing early apoptosis release apoptotic cell blebs via plasma membrane shedding, apoptotic cell exosome-like vesicles through fusion of MVBs with the cell membrane, and EVs generated by fragmentation of beaded apoptopodia. At later stages of apoptosis, cells disintegrate into apoptotic bodies, some containing small nuclear fragments. The final rest(s) of the apoptotic cell that does not undergo further disintegration and still bears most of the remaining of the cell nucleus is known as apoptotic cell body. Abbreviations: dsDNA, double stranded DNA; ILVs, intraluminal vesicles; MVB, multivesicular body.

Figure 2:. Effects of EVs on innate immunity.

Different types of EVs released by eukaryote cells under steady-state or pathological conditions and by bacteria, parasites or fungi, interact with soluble and cellular components of the innate immune system. Abbreviations: Ag, antigen; BM, bone marrow; DCs, dendritic cells; EVs, extracellular vesicles; I/R, ischemia / reperfusion; MAC, membrane attack complex; MØs, macrophages; MVs, microvesicles; OMVs, outer membrane vesicles; PMNs, polymorphonuclear leukocytes.