Schifferli, Jürg

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REVIEWMicrovesicles are messengersJürg A. SchifferliReceived: 25 April 2011 /Accepted: 4 May 2011 /Published online: 18 May 2011# Springer-Verlag 2011For years, we have rightly learned that communication inand between organisms depends on soluble mediators andcell-to-cell contact. The evidence that microvesiclesreleased by one cell might provide information to anothercell or is capable to modify the immediate and the distantenvironment emerged only over the last two decades(Fig. 1). Initially, such membrane-coated vesicles wereconsidered as waste to be eliminated or to correspond toactivating surfaces for coagulation. Only more recently didit became apparent that there was more to it. Thesevesicles transmitted messages—suppressive, activatingand/or modifying messages. Interestingly, even bacteriarelease vesicles, which seem to bulge from the outermembrane.Most cells release microvesicles, spontaneously orafter stimulation. Thus, this universal phenomenon may havetwo fundamental functions: get rid of unnecessary materialand transmit messages. In this series of reviews, the secondaspect will be mainly emphasized since many novel aspectshave emerged and merit attention. There has been noattempt to cover the whole field, but rather to illustratesome fundamental aspects, which are presently underinvestigations.First, bacteria produce vesicles. These outer membranevesicles (OMV) of gram-negative bacteria have revealed amechanism by which virulence factors can be concentratedand transmitted at a distance to other bacteria. Can Ünaland colleagues describe this phenomenon, discuss howthese vesicles can vehicle toxins, serve as activators [1] ordecoy for the immune system, but indicate as well, that ithas been possible to use OMV to our advantage, i.e. bymodifying and using them as vaccines. Indeed, the efficacyof the OMV-derived vaccine against the serotype Bmeningococci is around 90%; nothing similar has beenobtained by other methods to date. The idea to usemicrovesicles as vaccines has also been taken up by tumourimmunologists!Eukaryotic cells release different type of vesicles.Without matrix vesicles released by mineralizing cells, wewould be boneless and even teethless! The existence ofsuch vesicles was over a longer period of time disputed,until it was realized that they were essential for calcificationto take place. Ellis Golub describes the complex biologicalproperties of matrix vesicles [2]. He indicates, however, notonly the good side of these annexins and phosphatidyl-serine (PS) containing vesicles, but also that they areresponsible for pathological calcifications as seen inatherosclerotic plaques.But not all vesicles are shed from the cell surface asmatrix vesicles. There has been an extensive series ofstudies on the formation of exosomes, a type of vesicle thatis formed inside the cell and then secreted. Exosomes areproduced/stored in multivesicular bodies, express specificproteins of the endosomal compartments, and have acharacteristic size of around 50–100 nm. Initially describedin reticulocytes, they were found in many cells, includingimmune cells—in particular dendritic cells—and in tumourcells as well. Many groups of researchers have exploredthese exosomes in depth, their formation, the expression ofspecific molecules on their surface and of course theirpossible functions. Very interesting are the studies, whichdefine their immune response enhancing or blockingactivities. The Paris team has for more than a decadeexplored the potential role of dendritic cells in immuneThis article is published as part of the special issue on Small Vesicle asImmune Modulators [33:5]J. A. Schifferli (*)Department of Medicine, University Hospital Basel,Basel, Switzerlande-mail: j.schifferli@unibas.chSemin Immunopathol (2011) 33:393–394DOI 10.1007/s00281-011-0276-6responses (Nathalie Chaput and Clotilde Théry) [3].Douglas Taylor and Cicek Gercel-Taylor have definedexosomes of tumour cells and placenta [4] more than20 years ago and provided much evidence concerning theircapacity to modify their microenvironment. Both reviewpresent up to date knowledge in the field of exosomes.Exosomes transmit messages by their surface proteins andlipids. However, the observation that intra-vesicular compo-nents might transmit not only proteins, but also different typesof RNA and DNA has fascinating perspectives. Indeed, thecells taking up such materials might be modified profoundly.Tae Hon Lee and co-authors describe the “cargo” function ofexosomes, and show thanks to recent data obtained in theirown group how oncogenes are transmitted from tumour cellsto cells around the tumour—an oncogenic field effect [5]. It ispossible that such transfer of genetic material is part ofnormal biology and development as well.One should not forget that much initial work on micro-vesicles has been performed with platelets. Activated plateletsrelease a large number of microvesicles directly from the cellsurface (shed microvesicles=microparticles, also called ecto-somes) and exosomes. These microparticles express much PS,thus, allow coagulation to proceed. Olivier Morel andcolleagues describe this interaction between vesiclesoriginating from platelets and other cells found in bloodand the coagulation cascade, a field, to which they havecontributed extensively [6]. Evidently, there is more to itthan just coagulation, binding to endothelial and inflam-matory cells induces further reactions, which merit to beunderstood if we want to control pathological situationsrelated to excessive platelet activation.Salima Sadallah et al. review recent evidence that manycirculating cells release ectosomes, i.e. vesicles buddingdirectly from the cell surface. This has been known for along time for platelets and erythrocytes when attacked bycomplement. Interestingly, ectosomes released by polymor-phonuclear leukocytes, the very cells that enhance inflam-mation, have anti-inflammatory and immunomodulatoryactivities [7], probably because of the expression of PSsimilar to apoptotic cells.Indeed, apoptotic cells and bodies show a change in thedistribution of the membrane bi-layer phospholipids withPS being scrambled from the internal layer to the externalsurface. The high expression of PS and oxyPS induces theirphagocytosis by macrophages but also by by-standard cellswith induction of an anti-inflammatory/immunosuppressivereaction [8]. Benjamin Frey and Udo Gaipl recapitulatewhat is known about PS on apoptotic cells and micro-vesicles, so as to allow us to better understand the role ofPS expression under different conditions [9].References1. Vidakovics ML, Jendholm J, Mörgelin M, Månsson A, Larsson C,Cardell LO, Riesbeck K (2010) B cell activation by outer membranevesicles–a novel virulence mechanism. PLoS Pathog 15:e10007242. Kirsch T, Harrison G, Golub EE, Nah HD (2000) The roles of annexinsand types II and X collagen in matrix vesicle-mediated mineralizationof growth plate cartilage. J Biol Chem 275:35577–355833. Viaud S, Ploix S, Lapierre V, Théry C, Commere PH, TramalloniD, Gorrichon K, Virault-Rocroy P, Tursz T, Lantz O, Zitvogel L,Chaput N (2011) Updated technology to produce highly immuno-genic dendritic cell-derived exosomes of clinical grade: a criticalrole of interferon-γ. J Immunother 34:65–754. Sabapatha A, Gercel-Taylor C, Taylor DD (2006) Specific isolationof placenta-derived exosomes from the circulation of pregnantwomen and their immunoregulatory consequences. Am J ReprodImmunol 56:345–3555. Magnus N, Garnier D, Rak J (2010) Oncogenic epidermal growthfactor receptor up-regulates multiple elements of the tissue factorsignaling pathway in human glioma cells. Blood 116:815–8186. Morel O, Hugel B, Jesel L, Mallat Z, Lanza F, Douchet MP, ZupanM, Chauvin M, Cazenave JP, Tedgui A, Freyssinet JM, Toti F(2004) Circulating procoagulant microparticles and soluble GPV inmyocardial infarction treated by primary percutaneous transluminalcoronary angioplasty. A possible role for GPIIb-IIIa antagonists. JThromb Haemost 2:1118–11267. Eken C, Martin PJ, Sadallah S, Treves S, Schaller M, Schifferli JA(2010) Ectosomes released by polymorphonuclear neutrophilsinduce a MerTK-dependent anti-inflammatory pathway in macro-phages. J Biol Chem 285:39914–399218. Borisenko GG, Matsura T, Liu SX, Tyurin VA, Jianfei J, SerinkanFB, Kagan VE (2003) Macrophage recognition of externalizedphosphatidylserine and phagocytosis of apoptotic Jurkat cells–existence of a threshold. Arch Biochem Biophys 413:41–529. Frey B,Munoz LE, Pausch F, Sieber R, Franz S, Brachvogel B, PoschlE, Schneider H, Rödel F, Sauer R, Fietkau R, Herrmann M, Gaipl US(2009) The immune reaction against allogeneic necrotic cells isreduced in Annexin A5 knock out mice whose macrophages displayan anti-inflammatory phenotype. J Cell Mol Med 13:1391–1399Fig. 1 Intercellular communication in an organism or betweenorganisms394 Semin Immunopathol (2011) 33:393–394

Microvesicles are messengers

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Microvesicles are messengers

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