Large Extracellular Vesicles: Have We Found the Holy Grail of Inflammation?

Abstract

The terms microparticles (MPs) and microvesicles (MVs) refer to large extracellular vesicles (EVs) generated from a broad spectrum of cells upon its activation or death by apoptosis. The unique surface antigens of MPs/MVs allow for the identification of their cellular origin as well as its functional characterization. Two basic aspects of MP/MV functions in physiology and pathological conditions are widely considered. Firstly, it has become evident that large EVs have strong procoagulant properties. Secondly, experimental and clinical studies have shown that MPs/MVs play a crucial role in the pathophysiology of inflammation-associated disorders. A cardinal feature of these disorders is an enhanced generation of platelets-, endothelial-, and leukocyte-derived EVs. Nevertheless, anti-inflammatory effects of miscellaneous EV types have also been described, which provided important new insights into the large EV-inflammation axis. Advances in understanding the biology of MPs/MVs have led to the preparation of this review article aimed at discussing the association between large EVs and inflammation, depending on their cellular origin.

Keywords: endothelial-derived microvesicles; inflammation; leukocyte-derived microvesicles; microvesicles and exosomes; platelet-derived microvesicles.

Figure 1

Biogenesis of microvesicles (MVs) and exosomes. Unlike MVs, which are shedded directly from the plasma membrane, most exosomes are formed by invagination of endosomes and are stored within multivesicular bodies (MVBs) before release. Exosomes inside MVBs are also called intraluminal vesicles (ILVs). Upon fusion of MVBs with the plasma membrane exosomes are released into the extracellular environment. Both MVs and exosomes enclose greatly varying compositions of proteins, lipids, and nucleic acids and can be characterized by differing surface antigens.

Figure 2

Universal pro- and anti-inflammatory properties of MVs. The three main types of circulating MVs (PMVs, EMVs, and LMVs) exhibit common proinflammatory activities such as activation of immune cells (, , , , –119, 147, 150, 154, 156, 159, 160, 185), activation of endothelial cells (66, 72, 100, 101, 104, 108, 145, 146, 180, 181, 200, 202, 203), release of proinflammatory cytokines (, , , , , –, –187, 200, 201, 212, 214), enhanced leukocyte extravasation (101, 104, 108, 130, 150, 151), and mCRP generation (162, 163). They also have an anti-inflammatory effect, based on the inhibition of the release of proinflammatory cytokines (–134, 155, 209, 210).

Figure 3

The three types of MVs (PMVs, EMVs, and LMVs) are characterized by their unique anti-inflammatory properties. This applies to the following mechanisms: suppression of leukocyte activation (132, 135), suppression of endothelial cell activation (155), protective role in sepsis (170, 171, 204), and release of anti-inflammatory cytokines (209, 210, 212).