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Mast Cell Degranulation Is Accompanied by the Release of A Mast Cell Degranulation Is Accompanied by the Release of a Selective Subset of Extracellular Vesicles That Contain Mast Cell−Specific Proteases This information is current as of September 28, 2021. Tom Groot Kormelink, Ger J. A. Arkesteijn, Chris H. A. van de Lest, Willie J. C. Geerts, Soenita S. Goerdayal, Maarten A. F. Altelaar, Frank A. Redegeld, Esther N. M. Nolte-'t Hoen and Marca H. M. Wauben J Immunol 2016; 197:3382-3392; Prepublished online 12 Downloaded from September 2016; doi: 10.4049/jimmunol.1600614 http://www.jimmunol.org/content/197/8/3382 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2016/09/10/jimmunol.160061 Material 4.DCSupplemental References This article cites 75 articles, 26 of which you can access for free at: http://www.jimmunol.org/content/197/8/3382.full#ref-list-1 by guest on September 28, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Mast Cell Degranulation Is Accompanied by the Release of a Selective Subset of Extracellular Vesicles That Contain Mast Cell–Specific Proteases Tom Groot Kormelink,* Ger J. A. Arkesteijn,*,† Chris H. A. van de Lest,* Willie J. C. Geerts,‡ Soenita S. Goerdayal,x Maarten A. F. Altelaar,x Frank A. Redegeld,{ Esther N. M. Nolte-’t Hoen,* and Marca H. M. Wauben* 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 Downloaded from 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, degran- ulation was accompanied by the release of CD63+ EV, which correlated with release of the soluble mediator b-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 http://www.jimmunol.org/ 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-derivedEVshouldbeconsideredpotentially important immune regulators. The Journal of Immunology, 2016, 197: 3382–3392. ast cells (MC) are granular immune cells located lysosomes; de novo–synthesized lipid mediators; and de novo– throughout the body at mucosal, submucosal, and con- synthesized cytokines and chemokines (11). Large quantities of M nective tissues, especially at sites contacting the external preformed mediators can be released into the extracellular environment by guest on September 28, 2021 environment, as well as in secondary lymphoid tissues and surrounding within minutes after activation as the result of rapid fusion of secretory blood and lymph vessels (1, 2). In addition to the well-defined effector granules with the plasma membrane, a process known as degranulation function of MC in allergic disorders, increasing evidence shows that (12). Moreover, certain stimuli (e.g., TLR activation) induce the re- MC play a prominent role in modulating innate and adaptive im- lease of mediators in the absence of degranulation (13, 14). munity and that they are associated with the initiation and progression In addition to soluble mediators, viable cells are able to release of multiple immune disorders (reviewed in Refs. 3–5). The mecha- extracellular vesicles (EV) that play a role in intercellular com- nisms by which MC exert these effects are poorly defined, although munication and induce significant functional effects in different soluble mediator release and direct contact with other immune cells, (patho)physiological processes, such as immune responses (15, including dendritic cells and T cells, are likely to be involved (6–10). 16), cancer (17), and cardiovascular diseases (18). EV released by Upon activation, MC can release a variety of soluble mediators that viable cells are small vesicular structures, with the vast majority are generally categorized as preformed mediators (e.g., histamine, typically ranging from 50 to 200 nm in size. EV are composed proteases) that are stored in secretory granules, also termed secretory of selected lipids (forming a bilayer membrane), proteins, and *Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, The proteomics data presented in this article have been submitted to Vesiclepedia Utrecht University, 3584 CM Utrecht, the Netherlands; †Department of Infectious (www.microvesicles.org) under accession number Vesiclepedia_575. Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584 Address correspondence and reprint requests to Dr. Tom Groot Kormelink, Department of CL Utrecht, the Netherlands; ‡Biomolecular Imaging, Bijvoet Center, Utrecht Uni- x Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, versity, 3584 CH Utrecht, the Netherlands; Biomolecular Mass Spectrometry and Yalelaan 2, 3584 CM Utrecht, the Netherlands. E-mail address: [email protected] Proteomics Group, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH Utrecht, the Netherlands; The online version of this article contains supplemental material. and {Division of Pharmacology, Department of Pharmaceutical Sciences, Faculty of Abbreviations used in this article: BMDC, bone marrow–derived dendritic cell; Science, Utrecht University, 3584 CG Utrecht, the Netherlands BMP, bis(monoacylglycero)phosphate; c48/80, compound 48/80; CPA3, carboxy- ORCIDs: 0000-0003-2143-2825 (C.H.A.v.d.L.); 0000-0002-4530-7458 (W.J.C.G.); peptidase A3; CTMC, connective tissue–type MC; DNP-HSA, DNP-specific hu- 0000-0002-7893-8192 (S.S.G.); 0000-0003-0360-0311 (M.H.M.W.). man serum albumin; DNP-IgE, DNP-specific IgE; EV, extracellular vesicle; MC, mast cell; MC-EV, MC-derived EV; MMC, mucosal-type MC; mMCP, MC prote- Received for publication April 7, 2016. Accepted for publication August 12, 2016. ase; PMC, peritoneal MC; rest-EV, EV under unstimulated conditions; rw-FSC, This work was supported by the Netherlands Organisation for Scientific Research as part of reduced wide-angle forward scatter; SP, substance P; SpMC, spleen-derived MC; the research program Talent Scheme - Veni (Project 91614090). M.A.F.A. was supported by TEM, transmission electron microscopy; TX-100, Triton X-100; UC-BSA, ultracen- Vidi Grant 723.012.102 from the Netherlands Organisation for Scientific Research. The trifuged BSA. proteomics performed is part of the project Proteins At Work, which was financed by the Netherlands Organisation for Scientific Research as part of the National Roadmap Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 Large-Scale Research Facilities of the Netherlands (Project 184.032.201). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1600614 The Journal of Immunology 3383 nucleic acids (19). The composition differs between different cell Assays for MC activation types and depends on the cellular activation state (20). This selective To analyze IgE-mediated MC activation, SpMC and PMC were primed for incorporation of cargo determines where and how EV exert their 1.5 h or overnight with DNP-specific IgE (DNP-IgE), washed once in 1% function. EV are released into the environment by the fusion of FCS/RPMI 1640, and incubated with DNP-specific human serum albumin endosomal multivesicular bodies with the plasma membrane, (DNP-HSA; Sigma-Aldrich). Activation by compound 48/80 (c48/80), resulting in the release of their intraluminal vesicles, or by outward substance P (SP), or LPS (all from Sigma-Aldrich) was performed on nonprimed cells. Degranulation assays were performed on 0.65 3 106 cells/ml budding from the plasma membrane (19). It is
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