Treponemapalliduminducestheactivationofendothelialcellsviamacrophage-derivedexosomes|SpringerLink
Abstract

Recentstudieshaveshownthatexosomesplayaroleinpathogenesisandinthetreatmentofinflammatorydiseasesandtumours.WeexploredtheeffectsofTreponemapallidum-inducedmacrophage-derivedexosomesonvascularendothelialcellstodeterminewhethertheyareinvolvedinthepathogenesisofsyphilis.AsyphilisinfectionmodelwasestablishedusingrabbitstoharvestT.pallidumatthepeakofproliferation.Exosomesderivedfrommacrophageswereextractedusingcommercialkitsandcharacterizedbytransmissionelectronmicroscopy,westernblotassays,andnanoparticletrackinganalysis.SecretedcytokinelevelsandtheadhesionandpermeABIlityofhumanumbilicalveinendothelialcellswereevaluatedinaco-culturemodelusingtheextractedexosomes.TheresultsofthisstudyrevealedthatexosomesderivedfromT.pallidum-infectedmacrophagesenhancedcelladhesionandpermeability.Thelevelsofthesecretedcytokines,includingICAM-1,VCAM-1,VEGF,andIL-8werehigherintheexperimentalgroupthaninthecontrolgroup.OurfindingssuggestthatexosomesderivedfromT.pallidum-infectedmacrophagesaffectthecelladhesionandpermeabilityofvascularendothelialcells.Thesechangesmayplayimportantrolesinsyphilispathogenesis.ThisstudyisthefirsttorevealtheeffectsofexosomesderivedfromT.pallidum-infectedmacrophagesontheadhesion,permeability,andsecretedcytokinesofhumanumbilicalveinendothelialcells.

References1.

CaoY,SuX,WangQ,XueH,ZhuX,ZhangC,JiangJ,QiS,GongX,ZhuX,PanM,RenH,HuW,WeiZ,TianM,LiuW(2017)AmulticenterstudyevaluatingceftriaxoneandbenzathinepenicillinGastreatmentagentsforearlysyphilisinJiangsu,China.ClinInfectDis65(10):1683–1688.https://doi.org/10.1093/cid/cix611

ArticleCASPubMedGoogleScholar2.

WorldHealthOrganization(2016)Titleofthesubordinatedocument:In:Reportonglobalsexuallytransmittedinfectionsurveillance2015,pp14–27.https://www.who.int/reproductivehealth/publications/rtis/stissurveillance-2015/en

3.

Chinesecenterfordiseasecontrolandprevention(2018)Titleofthesubordinatedocument:In:Overviewofthenationallegalinfectiousdiseaseepidemicin2017.Chinesecenterfordiseasecontrolandprevention.http://www.nhfpc.gov.cn/jkj/s3578/201802/de926BDb046749abb7b0a8e23d929104.shtml.Accessed26Feb2018

4.

RileyBS,Oppenheimer-MarksN,RadolfJD,NorgardMV(1994)VirulentTreponemapallidumpromotesadhesionofleukocytestohumanvascularendothelialcells.InfectImmun62(10):4622–4625

CASPubMedPubMedCentralGoogleScholar5.

HoustonS,HofR,FrancescuttiT,HawkesA,BoulangerMJ,CameronCE(2011)BifunctionalroleoftheTreponemapallidumextracellularmatrixbindingadhesinTp0751.InfectImmun79:1386–1398.https://doi.org/10.1128/iai.01083-10

ArticleCASPubMedGoogleScholar6.

ZhangRL,WangQQ,ZhangJP,YangLJ(2015)Tp17membraneproteinofTreponemapallidumactivatesendothelialcellsinvitro.IntImmunopharmacol25(2):538–544.https://doi.org/10.1016/j.intimp.2015.02.028

ArticleCASPubMedGoogleScholar7.

ZhangRL,ZhangJP,WangQQ(2014)RecombinantTreponemapallidumproteinTp0965activatesendothelialcellsandincreasesthepermeabilityofendothelialcellmonolayer.PLoSOne9(12):e115134.https://doi.org/10.1016/j.intimp.2015.02.028

ArticleCASPubMedPubMedCentralGoogleScholar8.

GreeningDW,GopalSK,XuR,SimpsonRJ,ChenW(2015)Exosomesandtheirrolesinimmuneregulationandcancer.SeminCellDevBiol40:72–81.https://doi.org/10.1016/j.semcdb.2015.02.009

ArticleCASGoogleScholar9.

LiuX,LiQ,NiuX,HuB,ChenS,SongW,DingJ,ZhangC,WangY(2017)Exosomessecretedfromhuman-inducedpluripotentstemcell-derivedmesenchymalstemcellspreventosteonecrosisofthefemoralheadbypromotingangiogenesis.IntJBiolSci13(2):232–244.https://doi.org/10.7150/ijbs.16951

ArticleCASPubMedPubMedCentralGoogleScholar10.

Osada-OkaM,ShiotaM,IzumiY,NishiyamaM,TanakaM,YamaquchiT,SakuraiE,MiuraK,IwaoH(2017)Macrophage-derivedexosomesinduceinflammatoryfactorsinendothelialcellsunderhypertensiveconditions.HypertensRes40(4):353–360.https://doi.org/10.1038/hr.2016.163

ArticleCASPubMedGoogleScholar11.

HuiWW,HercikK,BelsareS,AluqubellyN,ClappB,RinaldiC,EdelmannMJ(2018)SalmonellaentericaSEROvartyphimuriumalterstheextracellularproteomeofmacrophagesandleadstotheproductionofproinflammatoryexosomes.InfectImmun86(2):e00386–e00317.https://doi.org/10.1128/IAI.00386-17

CASArticlePubMedPubMedCentralGoogleScholar12.

DalviP,SunB,TangN,PulliamL(2017)ImmuneactivatedmonocyteexosomesaltermicroRNAsinbrainendothelialcellsandinitiateaninflammatoryresponsethroughtheTLR4/MyD88pathway.SciRep7(1):9954.https://doi.org/10.1038/s41598-017-10449-0

ArticleCASPubMedPubMedCentralGoogleScholar13.

HawleyKL,CruzAR,BenjaminSJ,LaVakeCJ,CervantesJL,LeDoytM,RamirezLG,MandichD,Fiel-GanM,CaimanoMJ,RadolfJD,SalazarJC(2017)IFNγenhancesCD64-potentiatedphagocytosisofTreponemapallidumopsonizedwithhumansyphiliticserumbyhumanmacrophages.FrontImmunol8:1227.https://doi.org/10.3389/fimmu.2017.01227

ArticleCASPubMedPubMedCentralGoogleScholar14.

Marques-GarciaF,Isidoro-GarciaM(2016)ProtocolsforexosomeisolationandRNAprofiling.MethodsMolBiol1434:153–167.https://doi.org/10.1007/978-1-4939-3652-6_11

ArticleCASPubMedGoogleScholar15.

XuR,SimpsonRJ,GreeningDW(2017)Aprotocolforisolationandproteomiccharacterizationofdistinctextracellularvesiclesubtypesbysequentialcentrifugalultrafiltration.MethodsMolBiol1545:91–116.https://doi.org/10.1007/978-1-4939-6728-5_7

ArticleCASPubMedGoogleScholar16.

LobbRJ,BeckerM,WenSW,WongCS,WieqmansAP,LeimqruberA,MöllerA(2015)Optimizedexosomeisolationprotocolforcellculturesupernatantandhumanplasma.JExtracellVesicles4:27031.https://doi.org/10.3402/jev.v4.27031

ArticleGoogleScholar17.

McnicholasK,MichaelMZ(2017)Immuno-characterizationofexosomesusingnanoparticletrackinganalysis.MethodsMolBiol1545:35–42.https://doi.org/10.1007/978-1-4939-6728-5_3

ArticleCASPubMedGoogleScholar18.

VogelR,WillmottG,KozakD,RobertsGS,AndersonW,GroenewegenL,GlossopB,BarnettA,TurnerA,TrauM(2011)Quantitativesizingofnano/microparticleswithatunableelastomericporesensor.AnalChem83(9):3499–3506.https://doi.org/10.1021/ac200195n

ArticleCASPubMedGoogleScholar19.

WillmottGR,VogelR,YuSS,GroenewegenLG,RobertsGS,KozakD,AndersonW,TrauM(2010)Useoftunablenanoporeblockaderatestoinvestigatecolloidaldispersions.JPhysCondensMatter22(45):454116.https://doi.org/10.1088/0953-8984/22/45/454116

ArticleCASPubMedGoogleScholar20.

LuhderF,KebirH,OdoardiF,LitkeT,SonneckM,AlvarezJI,WinchenbachJ,EckertN,HayardenyL,SoraniE,LodyginD,FlugelA,PratA(2017)Laquinimodenhancescentralnervoussystembarrierfunctions.NeurobiolDis102:60–69.https://doi.org/10.1016/j.nbd.2017.02.002

ArticleCASPubMedGoogleScholar21.

WeiF,LiuS,LuoL,GuN,ZengY,ChenX,XuS,ZhangD(2017)Anti-inflammatorymechanismofulinastatin:InhibitingthehyperpermeabilityofvascularendothelialcellsinducedbyTNF-αviatheRhoA/ROCKsignalpathway.IntImmunopharmacol46:220–227.https://doi.org/10.1021/ac200195n

ArticleCASPubMedGoogleScholar22.

SellS,SalmanJ,NorrisSJ(1985)Reinfectionofchancre-immunerabbitswithTreponemapallidum.AmJPathol118:248–255.(PubMed:3881974)

CASPubMedPubMedCentralGoogleScholar23.

RadolfJD,ArndtLL,AkinsDR,CurettyLL,LeviME,ShenY,DavisLS,NorgardMV(1995)TreponemapallidumandBorreliaburgdorferilipoproteinsandsyntheticlipopeptidesactivatemonocytes/macrophages.JImmunol154(6):2866–2877

CASPubMedGoogleScholar24.

SellatiTJ,BouisDA,KitchensRL,DarveauRP,PuginJ,UlevitchRJ,GangloffSC,GoyertSM,NorgardMV,RadolfJD(1998)TreponemapallidumandBorreliaburgdorferilipoproteinsandsyntheticlipopeptidesactivatemonocyticcellsviaaCD14-dependentpathwaydistinctfromthatusedbylipopolysaccharide.JImmunol160(11):5455–5464

CASPubMedGoogleScholar25.

RadolfJD,DekaRK,AnandA,SmajsD,NorgardMV,YangXF(2016)Treponemapallidum,thesyphilisspiRochete:makingalivingasastealthpathogen.NatRevMicrobiol14:744–759.https://doi.org/10.1038/nrmicro.2016.141

ArticleCASPubMedPubMedCentralGoogleScholar26.

LiP,KaslanM,LeeSHetal(2017)Progressinexosomeisolationtechniques.Theranostics7(3):789–804.https://doi.org/10.7150/thno.18133

ArticleCASPubMedPubMedCentralGoogleScholar27.

KumarP,ShenQ,PivettiCD,LeeES,Wu.MH,Yuan.SY(2009)Molecularmechanismsofendothelialhyperpermeability:implicationsininflammation.ExpertRevMolMed11:e19.https://doi.org/10.1017/S1462399409001112

ArticlePubMedPubMedCentralGoogleScholar28.

ShiY,JiangX,ZhangL,PuH,HuX,ZhangW,CaiW,GaoY,LeakRK,KeepRF,BennettMV,ChenJ(2017)Endothelium-targetedoverexpressionofheatshockprotein27amelioratesblood-brainbarrierdisruptionafterischemicbraininjury.ProcNatlAcadSciUSA114(7):E1243–E1252.https://doi.org/10.1073/pnas.1621174114

ArticleCASPubMedGoogleScholar29.

FerraraN,GerberHP,LeCouterJ(2003)TheBIOLOGyofVEGFanditsreceptors.NatMed9(6):669–676.https://doi.org/10.1038/nm0603-669

ArticleCASPubMedGoogleScholar30.

ImE,ChoiYJ,KimCH,FiocchiC,PothoulakisC,RheeSH(2009)TheangiogeniceffectofprobioticBacilluspolyfermenticusonhumanintestinalmicrovascularendothelialcellsismediatedbyIL-8.AmJPhysiolGastrointestLiverPhysiol297(5):G999–G1008.https://doi.org/10.1152/ajpgi.00204.2009

ArticleCASPubMedPubMedCentralGoogleScholar

Downloadreferences

Acknowledgements

WethankProfessorTianciYang(ZhongshanHospital,MedicalCollegeofXiamenUniversity)forsupplyingusT.pallidum(Nicholsstrain)andtheNanjingMilitaryRegionCDCfortheirassistanceintheanimalexperiment.WeacknowledgeGuo-JunLiangandZhi-JuZhengfortheirsupportandassistance.WealsothankXiang-DongGongandFang-ZhiDufortheirassistancewithdataanalysis.

Funding

ThisstudywasfundedbytheUnionInnovationTeamProjectoftheChineseAcademyofMedicalSciences(2016-I2M-3021),theNationalNaturalScienceFoundationofChina(81772209and81601804),theNaturalScienceFoundationofJiangsuProvinceofChina(BK20150121),andthePUMCYouthFundoftheFundamentalResearchFundsfortheCentralUniversities(2017310056).Thefundershadnoroleinstudydesign,datacollectionandanalysis,decisiontopublish,orpreparationofthemanuscript.

AuthorinformationAffiliationsDepartmentofDermatology,AffiliatedPekingUniversityFirstHospitalofPekingUniversityHealthScienceCenter,Beijing,100083,ChinaBu-FangXuInstituteofDermatologyandSkinHospital,ChinaCenterforDiseasescontrolandPrevention,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollegeandNationalCenterforSTDControl,Nanjing,210042,ChinaQian-QiuWang, Jing-PingZhang  Wen-LongHuDepartmentofDermatology,AffiliatedWuxiNo.2People’sHospitalofNanjingMedicalUniversity,Wuxi,214002,ChinaRui-LiZhangAuthorsBu-FangXuViewauthorpublicationsYoucanalsosearchforthisauthorinPubMedGoogleScholarQian-QiuWangViewauthorpublicationsYoucanalsosearchforthisauthorinPubMedGoogleScholarJing-PingZhangViewauthorpublicationsYoucanalsosearchforthisauthorinPubMedGoogleScholarWen-LongHuViewauthorpublicationsYoucanalsosearchforthisauthorinPubMedGoogleScholarRui-LiZhangViewauthorpublicationsYoucanalsosearchforthisauthorinPubMedGoogleScholarContributions

Q-QW,R-LZ,andB-FXconceivedtheexperiments.B-FXconductedtheexperiments.Q-QW,B-FX,andW-LHanalysedtheresults.B-FXandQ-QWwrotethemanuscript.Allauthorscontributedtothereviewofthemanuscript.

Correspondingauthors

CorrespondencetoQian-QiuWangorRui-LiZhang.

Ethicsdeclarations
Conflictofinterest

Theauthorshavedeclaredthatnocompetinginterestsexist.