Extracellular vesicles and their content in bioactive lipid mediators: more than a sack of microRNA

Abstract

Extracellular vesicles (EVs), such as exosomes and microvesicles, are small membrane-bound vesicles released by cells under various conditions. In a multitude of physiological and pathological conditions, EVs contribute to intercellular communication by facilitating exchange of material between cells. Rapidly growing interest is aimed at better understanding EV function and their use as biomarkers. The vast EV cargo includes cytokines, growth factors, organelles, nucleic acids (messenger and micro RNA), and transcription factors. A large proportion of research dedicated to EVs is focused on their microRNA cargo; however, much less is known about other EV constituents, in particular, eicosanoids. These potent bioactive lipid mediators, derived from arachidonic acid, are shuttled in EVs along with the enzymes in charge of their synthesis. In the extracellular milieu, EVs also interact with secreted phospholipases to generate eicosanoids, which then regulate the transfer of cargo into a cellular recipient. Eicosanoids are useful as biomarkers and contribute to a variety of biological functions, including modulation of distal immune responses. Here, we review the reported roles of eicosanoids conveyed by EVs and describe their potential as biomarkers.

Keywords: cancer; eicosanoids; exosomes; microvesicles; neutrophils; platelets.

Fig. 1.

Eicosanoids and the associated enzymes are comprised in EVs. Cells produce different types of EVs, such as exosomes and microvesicles. Exosomes are stored in multivesicular bodies (MVBs) and released on cell activation, whereas microvesicles are generated by plasma membrane budding and shedding. Graphic representation of the metabolism of AA into eicosanoids. AA, arachidonic acid; COX-1, cyclooxygenase-1; COX-2, cyclooxygenase-2; TX, thromboxane; 12-LO, 12-lipoxygenase; 5-LO, 5-lipoxygenase; LT, leukotriene; PG, prostaglandin; HETE ; hydroxyeicosatetraenoic acid.

Fig. 2.

Platelet-derived EVs participate in intercellular communication through their eicosanoid content. Platelets are highly proficient at releasing EVs, such as microvesicles (microparticles). EVs from activated platelets contain a broad cargo, which includes cytokines, transcription factors, cytokines, mitochondria, and nucleic acid. Of importance is the content in active cyclooxygenase-1 (COX-1) and 12-lipoxygenase (12-LO). In the presence of secreted phospholipase A₂ (sPLA₂) in an inflammatory milieu, platelet-derived EVs generate arachidonic acid, which can be metabolized into prostaglandin H₂ (PGH₂) and subsequently into prostacyclin (PGI₂) by the PGI synthase (PGIS) in endothelial cells. AA liberated by platelet-derived EVs can also undero lipoxygenation by the 12-LO itself present in platelet-derived EVs. Moreover, exogenous AA can be metabolized by platelet-derived EVs by 12-LO. 12-hydroxyeicosatetranoic acid (12-HETE) is generated and promotes the internalization of platelet EVs by neutrophils, thereby permitting efficient transfer of cargo. The internalization of platelet-EVs is therefore tightly regulated by the eicosanoid 12-HETE.

Fig. 3.

Neutrophils produce extracellular vesicles rich in eicosanoid components. When neutrophils are activated by the bacterial peptide N-formylmethionyl-leucyl-phenylalanine, they release exosomes containing leukotriene B₄ (LTB₄), which form a gradient. The gradient of LTB₄ forms an “exosome trail” that extends from the EV-producing cell and is necessary in neutrophil recruitment to the site of inflammation. EVs from neutrophils also contain arachidonic acid (AA), which upon capture by platelets, is metabolized into thromboxane A₂ (TxA₂). Thromboxane A₂ generated through the intercellular communication between neutrophils and platelets promotes inflammation and pathogen clearance in lungs in a bacterial infection model. 5-LO, 5-lipoxygenase; MVB, multivesicular body.