Mast Cell Degranulation Is Accompanied by the Release of a Selective Subset of Extracellular Vesicles That Contain Mast Cell–Specific Proteases

Abstract

Mast cells (MC) are well known for their effector role in allergic disorders; moreover, they are associated with diverse modulatory effects in innate and adaptive immunity. It is largely unclear how MC exert these modulating functions. In this article, we show that IgE-mediated MC degranulation leads to a rapid release of high quantities of extracellular vesicles (EV), comparable to the release of preformed mediators. EV are submicron structures composed of lipid bilayers, proteins, and nucleic acids that are released by cells in a regulated fashion and are involved in intercellular communication. Primary murine mucosal-type MC and connective tissue-type MC released phenotypically different EV populations depending on the stimulus they received. Although unstimulated MC constitutively released CD9 EV, degranulation was accompanied by the release of CD63 EV, which correlated with release of the soluble mediator β-hexosaminidase. This CD63 EV subset was smaller and exhibited a higher buoyant density and distinct phospholipid composition compared with CD9 EV. Marked differences were observed for phosphatidylinositol, phosphatidic acid, and bis(monoacylglycero)phosphate species. Strikingly, proteomic analysis of CD63 EV from connective tissue-type MC unveiled an abundance of MC-specific proteases. With regard to carboxypeptidase A3, it was confirmed that the enzyme was EV associated and biologically active. Our data demonstrate that, depending on their activation status, MC release distinct EV subsets that differ in composition and protease activity and are indicative of differential immunological functions. Concerning the strategic tissue distribution of MC and the presence of degranulated MC in various (allergic) disorders, MC-derived EV should be considered potentially important immune regulators.

Mastocytosis-derived extracellular vesicles exhibit a mast cell signature, transfer KIT to stellate cells, and promote their activation

“…Extracellular vesicles (EVs), such as exosomes (40-150 nm in diameter) and microvesicles (50-1,000 nm in diameter), are released to some degree by most types of cells including mast cells (10,11), dendritic cells (12,13), natural killer cells (14), intestinal epithelial cells (15), and B lymphocytes (16). They are also released by cancerous cells including those in hematological malignancies (17,18), which may generate a greater number of exosomes than normal cells (19,20).…”

Characterization and Analysis of The Nasal Microbiota and Plasmatic Extracellular Vesicles in Allergic Rhinitis: A Case-Control Study

“…The greatest differences of EVs subpopulations between AR patients and HS group were identi ed for platelets, endothelium, mastocytes and eosinophil derived EVs. Indeed, during a proin ammatory stimulus an increased amount of EVs released by both platelets and endothelium has been already identi ed as well as for mastocytes derived EVs, speci cally found in greater concentration during an IgE based immune response, a speci c signature of allergic conditions [67][68][69]. The effects of EVs released by mastocytes was also linked to the maturation of the dendritic cells, critical players and sentinels of the immune system in the nasal mucosa during AR [70,71].…”

Extracellular Vesicles as Mediators of Cellular Crosstalk Between Immune System and Kidney Graft

“…MC-derived EVs contain p-MHC complexes or endocytosisderived antigens and can be released by both activated and resting BM-MCs. The main target of these particles is DCs and other professional APCs (51,80,81). Skokos et al investigated the role of MCs in allo-antigen presentation; the authors observed that ovalbumin was more effectively recognized by T cell if taken up by MCs and then transferred to DCs rather than presented directly by DCs (57).…”