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2011Nanovesicles from Malassezia sympodialis and Host

NanovesiclesfromMalasseziasympodialisandHostExosomesInduceCytokineResponses–Novel

MechanismsforHost-MicrobeInteractionsinAtopicEczema

UlfGehrmann1*,KhaledaRahmanQazi1,CatharinaJohansson1,KjellHultenby2,MariaKarlsson3,LenaLundeberg3,SusanneGabrielsson1.,AnnikaScheynius1.

1ClinicalAllergyResearchUnit,DepartmentofMedicineSolna,KarolinskaInstitutet,Stockholm,Sweden,2DepartmentofLaboratoryMedicine,KarolinskaUniversityHospitalHuddinge,Huddinge,Sweden,3DermatologyandVenereologyUnit,KarolinskaUniversityHospital,Stockholm,Sweden

Abstract

Background:Intercellularcommunicationcanoccurviathereleaseofmembranevesicles.Exosomesarenanovesiclesreleasedfromtheendosomalcompartmentofcells.Dependingontheircelloforiginandtheircargotheycanexertdifferentimmunoregulatoryfunctions.Recently,fungiwerefoundtoproduceextracellularvesiclesthatcaninfluencehost-microbeinteractions.TheyeastMalasseziasympodialiswhichbelongstoournormalcutaneousmicrobialfloraelicitsspecificIgE-andT-cellreactivityinapproximately50%ofadultpatientswithatopiceczema(AE).Whetherexosomesorothervesiclescontributetotheinflammationhasnotyetbeeninvestigated.

Objective:ToinvestigateifM.sympodialiscanreleasenanovesiclesandwhethertheyorendogenousexosomescanactivatePBMCfromAEpatientssensitizedtoM.sympodialis.

Methods:ExtracellularnanovesiclesisolatedfromM.sympodialis,co-culturesofM.sympodialisanddendriticcells,andfromplasmaofpatientswithAEandhealthycontrols(HC)werecharacterisedusingflowcytometry,sucrosegradientcentrifugation,Westernblotandelectronmicroscopy.TheirabilitytostimulateIL-4andTNF-alpharesponsesinautologousCD14,CD34depletedPBMCwasdeterminedusingELISPOTandELISA,respectively.

Results:WeshowforthefirsttimethatM.sympodialisreleasesextracellularvesiclescarryingallergen.ThesevesiclescaninduceIL-4andTNF-aresponseswithasignificantlyhigherIL-4productioninpatientscomparedtoHC.ExosomesfromdendriticcellandM.sympodialisco-culturesinducedIL-4andTNF-aresponsesinautologousCD14,CD34depletedPBMCofAEpatientsandHCwhileplasmaexosomesinducedTNF-abutnotIL-4inundepletedPBMC.

Conclusions:ExtracellularvesiclesfromM.sympodialis,dendriticcellsandplasmacancontributetocytokineresponsesinCD14,CD34depletedandundepletedPBMCofAEpatientsandHC.Thesenovelobservationshaveimplicationsforunderstandinghost-microbeinteractionsinthepathogenesisofAE.

Citation:GehrmannU,QaziKR,JohanssonC,HultenbyK,KarlssonM,etal.(2011)NanovesiclesfromMalasseziasympodialisandHostExosomesInduceCytokineResponses–NovelMechanismsforHost-MicrobeInteractionsinAtopicEczema.PLoSONE6(7):e21480.doi:10.1371/journal.pone.0021480´(CRP-Sante´),LuxembourgEditor:JacquesZimmer,CentredeRecherchePublicdelaSante

ReceivedMarch1,2011;AcceptedJune2,2011;PublishedJuly22,2011

Copyright:ß2011Gehrmannetal.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense,whichpermits

unrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited.

Funding:ThisworkwassupportedbytheSwedishResearchCouncil(www.vr.se),CenterforAllergyResearchKarolinskaInstitutet(ki.se/ki/jsp/polopoly.jsp?d=4477&l=en),theHesselmanFoundation,theSwedishHeartandLungAssociation(http://www.hjart-lungfonden.se),theGroshinskyMemoryFoundation,theSwedishSocietyforMedicalResearch(SSMF,www.ssmf.se),theCancerandAllergyAssociation,theSwedishAsthmaandAllergyAssociation’sResearchFoundation(www.astmaoallergiforbundet.se),andthroughtheregionalagreementonmedicaltrainingandclinicalresearch(ALF)betweenStockholmCountyCouncilandtheKarolinskaInstitutet(ki.se/ki/jsp/polopoly.jsp;jsessionid=a3fQhAvJt7chzjc6I5?l=en&d=7121).U.G.holdsaPhDgrantfromKarolinskaInstitutet(ki.se/ki/jsp/polopoly.jsp?l=en&d=13467).Thefundershadnoroleinstudydesign,datacollectionandanalysis,decisiontopublish,orpreparationofthemanuscript.

CompetingInterests:Theauthorshavedeclaredthatnocompetinginterestsexist.*E-mail:ulf.gehrmann@ki.se

.Theseauthorscontributedequallytothiswork.

Introduction

Exosomesarenanovesicles(30–100nm)ofendosomaloriginproducedbydifferentcells[1,2,3].Theycanbesecretedintotheextracellularspaceandactasmeansofintercellularcommunica-tionbytransferringfunctionalproteinsandRNAmoleculesbetweencells[4,5].Theycanalsocarryantigensfrommicroor-ganismssuchasvirusesandbacteria[6,7].Exosomescanbeisolatedfrombodyfluidssuchasplasma[8],bronchoalveolarlavage(BAL)fluid[9],breastmilk[10]andurine[11].PreviousstudieshavefoundthatB-cellsanddendriticcells(DC)releaseMHCclassIIcontainingexosomeswhichcouldactivateimmuneresponsesinvitroandinvivo[12,13].Duetotheirimmunostimu-latorycapacity,exosomesfromantigenpresentingdendriticcells

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