2015 12 papsbrs 大會 - derma.org.t · often are required to trigger disease. th2 cytokines can...
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20144
201512PAPSBRS
The5thAnnualCongressofPanAsianPacificSkinBarrierResearchSociety
4*(35())201512(PAPSBRS)*: PAPSBRS 14 9(54)74
DATE:November22(W6),2014VENUE:Tainan,Taiwan Organizer:TaiwaneseDermatologicalAssociation
PanAsianPacificSkinBarrierResearchSociety
5th PAPSBRS
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PeterM.EliasEDUCATION:StanfordUniversity,Stanford,CaliforniaB.A. 1963UniversityofCalifornia,SanFrancisco M.D. 1967UniversityofCalifornia,SanFrancisco M.S. 1975BOARDCERTIFICATION:Dermatology 1973Dermatopathology1979PROFESSIONALAPPOINTMENTS: AssistantProfessor,DepartmentofDermatology,UniversityofCalifornia,SanFrancisco,
California 19741979
AssociateProfessorofDermatology 19791985
Chief,DermatologyService,VeteransAdministrationHospital,SanFrancisco, 19751997
ProfessorandViceChairman,DepartmentofDermatologyUniversityofCalifornia,San
Francisco,CA 1985pres
Chairman,FieldAdvisoryGroup,Veterans AdministrationCentralOffice 19801983
CouncilonGovernmentalLiaison,AmericanAcademyofDermatology 19801983
MedicalandScientificCommittee,DermatologyFoundation 19831987
Dr.Eliasisinlargepartresponsibleforthepresentwealthofknowledgeonboththestructureandmyriadfunctionsofmammalianstratumcorneum. Hispioneeringresearchsincethe1970'shasdispelledthemythofthestratumcorneumasa"dead,keratinized,basketweave"structure,toestablishtheiconic"brickandmortar"model. Throughhisefforts,thestratumcorneumisnowviewedasametabolicallyactive,twocompartmentcompositethatfunctionsasabiosensor. Theresultant"outsidein"conceptofthebarrierasaprimemoverinthepathogenesisofcutaneousdiseasehasalsobeenahighlightofDr.Elias'work,withtheparamountroleofskinbarrierdysfunctionindiseasepathogenesisnowwidelyrecognized.Overthepast30plusyears,Dr.Elias'labhasbeenthedestinationformorethan70younginvestigators,representingmultiplecountries,atrendthatstillcontinuestoenrichthefieldofacademicdermatologywithanarmamentariumoftechniquesanddisciplinesonthecuttingedgeofscienceonepidermalstructureandfunction. Dr.
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Eliascontinuestomentorhisvastnetworkofassociatesandpostdoctoralfellows,pastandpresent,severalofwhomhaveachievedleadershiprolesinacademiaandindustrytheworldover. Hisoeuvrecomprisesover600scientificpublications,thegreatmajorityofwhichappearinhighimpact,peerreviewedjournals,andincludingseveralbooksthathehaseithereditedorcoedited. Theeverincreasingimpactofhiscontinuedworkoncutaneousbiologyisreadilyevidentwithareviewofhiscontributionstotheliteratureduringthepastfiveyearsalone(i.e.,>120publishedmanuscripts),withcoauthorshipofmorethan90abstracts/presentationsattheAnnualMeetingsoftheSocietyforInvestigativeDermatologysince2003.RecentArticles:Eichenfield,L.F.,Elias,P.M.,Folwer,J.F.,Horowitz,P.,McLeod,R.P.Understandingskinbarrierdifferences:ademographic,cultural,andmedicaldiversityviewpoint.SeminCutMed&Surgery.32(2S):S16S20,June,2013.Feingold,K.R.,Elias,P.M. Roleoflipidsintheformationandmaintenanceofthecutaneouspermeabilitybarrer.BBAMolecularandCellBiologyofLipids.OnlinePublication,November,2013.Tiganescu,A.,Hupe,M.,Uchida,Y.,Mauro,T.M.,Elias,P.M.,Holleran,W.M.Increasedglucocorticoidactivationduringmouseskinwoundhealing.JEndocrin.OnlinePublication,Jan,2014.Elias,P.M.,Williams,M.L.,Cho,EH.,Feingold,K.R.Roleofcholesterolsulfateinepidermalstructureandfunction:lessonsfromxlinkedichthyosis.BBAMolecularandCellBiologyofLipids.OnlinePublication,Feb.2014.
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Abnormalitiesinthelamellarbodysecretorysystemunderline
thepathogenesisofatopicdermatitis
Ireviewherehowdiverseinheritedandacquiredabnormalitiesinepidermal
structuralandenzymaticproteinsconvergetoproducedefectivepermeabilitybarrier
functionandantimicrobialdefenseinAD.Althoughbestknownaremutationsin
filaggrin(FLG),mutationsinothermemberofthefusedS100familyofproteins(i.e.,
hornerin[hrn]andfilaggrin2[flg2]);thecornifiedenvelopeprecursor(e.g.,SPRR3);
mattrin,encodedbyTmem79,whichregulatestheassemblyoflamellarbodies;
SPINK5,whichencodestheserineproteaseinhibitor,LEKTI1;andthefattyacid
transporter,FATP4,haveallbeenlinkedtoAD.Yet,theseabnormalitiesoftenonly
predisposetoAD;additionalacquiredstressorsthatfurthercompromisebarrier
function;e.g.,psychologicalstress,alowambienthumidity,orhighpHsurfactants,
oftenarerequiredtotriggerdisease.Th2cytokinescanalsocompromisebarrier
functionbydownregulatingexpressionofmultipleepidermalstructuralproteins,
lipidsyntheticenzymesandantimicrobialpeptides.Alloftheseinheritedand
acquiredabnormalitiesconvergeonthelamellarbodysecretorysystem,producing
abnormalitiesinlipidcomposition,secretionand/orextracellularlamellarmembrane
organization,aswellasinantimicrobialdefense.Finally,Ibrieflyreviewtherapeutic
optionsthataddressthisnewpathogenicparadigm.
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ShigetoshiSanoEDUCATION:AlbertEinsteinMedicalCollege,
ImmunologyPostdoc.198892
OsakaUniversityGraduateSchoolof
Medicine,ImmunologyPh.D.1988
EhimeUniversityMedicalSchool(Japan)
M.D.1983POSITIONS:Since2007:ProfessorofDermatology,Chair,KochiMedicalSchool,KochiUniversity
20062007:AssociateProfessor,DepartmentofDermatology,OsakaUniversityMedicalSchool.
20052006:AssisstantProfessor,DepartmentofDermatology,OsakaUniversityMedicalSchool.
20042005:DirectorofDermatology,SumitomoHospital,Osaka
20032004:VisitingAssisstantProfessor,DepartmentofCarcinogenesis,MDAndersonCancerCenter
19942003:AssisstantProfessor,DepartmentofDermatology,OsakaUniversityMedicalSchool.
19921994:ClinicalDirectorofDermatology,SakaiMunicipalHospital,Osaka.
19831984: ResidentinOsakaUniversityHospital(Dermatology).
HONORSANDAWARD:2008: RohtoAward.2006: JapaneseSocietyofInvestigativeDermatology(JSID)Award.2005: EugeneFarberAward.2001: GaldermaAward.2000: MinamiAward(BestresearchawardfordermatologyinJapan).SELECTEDPUBLICATIONS20082014:YokigawaM,TakaishiM,NakajimaK,KamijimaR,FujimotoC,KataokaS,TeradaY,SanoS.Epicutaneousapplicationoftolllikereceptor7agonistsleadstosystemicautoimmunityinwildtypemice:anewmodelfosystemiclupuserythematosus,ArthritisRheumatol.66:694706,2014(Correspondingauthor)NakajimaK,TeraoM,TakaishiM,KataokaS,GotoInoueN,SetouM,HorieK,SakamotoF,ItoM,AzukizawaH,KitabaS,MurotaH,ItamiS,KatayamaI,TakedaJ,
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SanoS.Barrierabnormalityduetoceramidedeficiencyleadstopsoriasforminflammationinamousemodel.JInvestDermatol,133:255565,2013(Correspondingauthor)HiraiT,KandaT,SatoK,TakaishiM,NakajimaK,YamamotoM,KamijimaR,DiGiovanniJ,SanoS.CathepsinKisinvolvedindevelopmentofpsoriasislikeskinlesionsthroughTLRdependentTh17activation.JImmunol,190:480511,2013(Correspondingauthor)YokogawaM,TakaishiM,NakajimaK,KamijimaR,DiGiovanniJ,SanoS.ImiquimodattenuatesthegrowthofUVBinducedSCCinmicethroughTh1/Th17cells.MolCarcinog,52:7609,2013(Correspondingauthor)TakataT,TaniguchiY,OhnishiT,KohsakiS,NagamiM,NakajimaH,KumonY,TeradaY,TarutaniM,SanoS.FDGPET/CTisapowerfultoolfordetectingsubclinicalarthritisinpatientswithpsoriaticarthritisand/orpsoriasisvulgaris.JDermatolSci,64:1447,2011(Correspondingauthor)NakajimaK,KandaT,TakaishiM,ShigaT,MiyoshiK,NakajimaH,KamijimaR,TarutaniM,BensonJM,EllosoMM,GutshallLL,NasoMF,IwakumaY,DiGiovanniJ,SanoS.DistinctrolesofIL23andIL17inthedevelopmentofpsoriasislikelesionsinamousemodel.JImmunol,186:44819,2011(Correspondingauthor)MiyoshiK,TakaishiM,NakajimaK,IkedaM,KandaT,TarutaniM,IiyamaT,AsaoN,DiGiovanniJ,SanoS.Stat3asatherapeutictargetforthetreatmentofpsoriasis:aclinicalfeasibilitystudywithSTA21,aStat3inhibitor.JInvestDermatol,131:10817,2011(Correspondingauthor)ChanKS,SanoS(Cofirstauthor),KataokaK,AbelE,CarbajalS,BeltranL,CliffordJ, PeaveyM,ShenJ,DigiovanniJ.ForcedexpressionofaconstitutivelyactiveformofStat3inmouseepidermisenhancesmalignantprogressionofskintumorsinducedbytwostagecarcinogenesis.Oncogene,40:4045,2008SanoS,ChanKS,DigiovanniJ.ImpactofStat3activationuponskinbiology:Adichotomyofitsrolebetweenhomeostasisanddiseases.JDermatolSci50114,2008(Correspondingauthor)
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Barrierabnormalityinpsoriasisinhumanandmousestudies
ShigetoshiSano,M.D.,Ph.D.DepartmentofDermatology,KochiMedicalSchool,KochiUniversity,Japan
Inflammatory skindiseasesareoftenassociatedwithdisruptionof the skinbarrier
function, although the cause and effect relationship is complex. Like atopic
dermatitis (AD),psoriasispatients show abnormality in theepidermalbarrier. It is
unsolved whether the abnormal barrier function is the cause of psoriasis or
secondary to abnormal immune response, while susceptibility genes of psoriasis
includethoseencodingboth immunesystem(e.g.,IL23R)andbarrierfunction(e.g.,
LCE3B_C). Koebner phenomenon indicates that epidermal injury initiates the
formation of psoriatic lesions. On the other hand, occlusion (barrier restoration)
reverses psoriatic lesions. Therefore, the barrier dysfunctionmight contribute to
initiationandworseningofpsoriasis.
Ithasbeenreported thatceramidesaresignificantlydecreased in theepidermisof
patientswith psoriasis aswell as AD (Melnik et al., 1988; Imokawa et al., 1991;
Holleranetal.,1991;Mottaetal.,1993;Mottaetal.,1994;Alessandrinietal.,2004).
Arecentstudydemonstratedthatserinepalmytoiltransferase(SPT),theratelimiting
enzymefordenovoceramidebiosynthesisis,significantlyreducedinpsoriaticlesions
comparedwithuninvolved skin, and is inversely correlatedwith thepsoriasis area
severity index(PASI)score(Hongetal.,2007). Inthepresentstudy,weconfirmeda
decreaseinceramidelevelsinpsoriaticlesionscomparedtonormalepidermis.
To investigatewhether the SPTdeficiencyand the resulting reductionof ceramide
levelsintheepidermiswouldleadtoaninflammatoryskindiseaselikepsoriasis,we
generated keratinocytespecific SPT gene targeted mice. The mutant mice
demonstrated a decreased level of ceramides in the epidermis and barrier
dysfunctionwith increased transepidermalwater loss (TEWL). Interestingly, those
mice developed psoriasislike skin lesionswith upregulation of the IL23/17
pathway,whichisreminiscentoftheIL23/Th17axisinhumanpsoriasis(Fitchetal.,
2007). The present study reveals a pathogenic link between the primary barrier
disruption due to ceramide deficiency and immune responses that lead to
psoriasislike skin inflammation. K5.Stat3C, another distinguishedmousemodel of
psoriasis, also exhibited barrier dysfunction and therefore, tapestripping leads to
developmentofpsoriasislikelesion.
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MaoQiangMan
MaoQiangMangraduatedfromBinzhou
MedicalCollegeinChinain1982and
completedpostdoctoraltrainingatUniversity
ofCaliforniaSanFrancisco.Nowheisa
researchscientistatNorthernCalifornia
InstituteforResearchandEducation.His
researchinterestisregulationofepidermalpermeabilitybarrierfunction,andthe
linkofepidermalpermeabilitybarriertoskinagingandthepathogenesisofskin
disorders.Hehaspublishedover130papersinreputedjournalsandservingasan
editorialboardmemberandinvitedreviewerforanumberofscientificjournals.His
currentHindexis46.
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TheRoleofEpidermalFunctioninthePathogenesisofPsoriasis
MaoQiangMan,GeorgeMan,PeterM.EliasDermatologyServices,VeteransAffairMedicalCenterandUniversityofCaliforniaSanFrancisco,CA,USAPsoriasishaslongbeenconsideredtobeanimmunologicallyinitiateddisorderbasedonlaboratoryandclinicalevidence. Genetically,somepsoriasissusceptibilitylociareassociatedwithimmunefunctionsuchascytokineproductionandTcelldifferentiation;Psoriasisandautoimmunediseasessharesomesusceptibilitygenes.Clinically,psoriaticlesionsarefeaturedbyinflammationincludingincreasedcytokineexpression,andbothTcellanddendriticcellinfiltration. Yet,someevidencesuggeststhatpsoriasiscouldbedrivenbyaprimarydefectinepidermalfunction. Theflareofpsoriasisoftenoccursinlowerhumidityseasonsandregions. StudieshaveshownthatstratumcorneumhydrationislowerwhilebasaltransepidermalwaterlossratesandskinsurfacepHarehigherduringwinterthanduringsummer. Lowstratumcorneumhydrationalonehassubstantialimpactoncutaneousfunction,includinginductionofpruritus,stimulationofepidermalproliferationandcutaneousinflammation. Scratchingresultingfromlowhumidityinducedprurituscancausefurtherdamagetotheepidermalpermeabilitybarrier. Moreover,higherskinsurfacepHalonedelaysbarrierrecovery. Duringlowhumidityseasons,mechanicaltrauma,i.e,scratchingandabrasion,inducedbarrierdamagewouldberepairedmoreslowlyduetothehigherstratumcorneumpH. DefectivepermeabilitybarriernotonlyfurtherincreasesstratumcorneumpH,butalsostimulatesepidermalproliferation,cytokineproduction,inflammatoryinfiltration,aswellasepidermalvascularendothelialgrowthfactorproduction,leadingtodermalcapillaryproliferation,allofwhichareprominentfeaturesofpsoriasis. Furthermore,barrierdisruptiondecreasesexpressionlevelsoffilaggrinandcornifiedenvelopeprotein,whichwillalsodelaybarrierrepair. Innormalsubjects,thenegativeimpactofexogenousstressorsonepidermalfunctioncanbereadilyovercomeorminimized. Incontrast,insubjectsbearingpsoriasissusceptibilitygenes,alterationsofepidermalfunctioninducedbyexogenousstressorscannotberepairedrapidly,duetothosegeneticdefects. Asustainedbarrierdefectprovokesexcesskeratinocyteproliferationandinflammation,leadingtothedevelopmentofpsoriasis. Thus,psoriasisislikelyduetopermeabilitybarrierassociatedgeneticdefectsandistriggeredbyexternalstressors. Accordingly,psoriasiscouldbepossiblypreventedbyinterveningwiththeexogenousstressorsonepidermalfunction.
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Figure1RegulatoryRolesofEpidermalPermeabilityBarrierinCutaneousFunction.Theepidermalpermeabilitybarrierplayscrucialregulatoryrolesincutaneousfunctions.Disruptionofepidermalpermeabilitybarrierinitiatesawiderangeofcutaneousbiologicalresponses,includingepidermalproliferation,inflammation,andantimicrobialdefense.Decreasedpermeabilitybarrierinducesinflammationandepidermalproliferation,whichcantriggerandexacerbatecertainskindisorders,suchaspruritus,psoriasis,dermatitisaswellasskininfection.Meanwhilebarrierdisruptioninducedepidermalproliferation,lipidproduction/secretionandantimicrobialpeptideexpressionalsoresultinnormalizationofepidermalpermeabilitybarrier,whichinturninhibitcutaneousinflammationandinfection.Approachesthatenhanceepidermalpermeabilitybarriercouldbeanalternativeforpreventingandtreatingcertaindermatoses,includingpruritus,psoriasisanddermatitis.
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Figure2SchematicDiagramofEpidermalRoleinthePathogenesisofPsoriasis.Duetoprimarygeneticdefects,theepidermalpermeabilitybarrierisvulnerableinpsoriaticsubjects.Mechanicaltraumas,suchasscratchesorabrasion,damagetheskinbarrier,especiallyduringlowhumidityseasons,suchasthewinter.Whilebarrierfunctioncanbereadilymaintainedinnormalsubjects,inpsoriaticpatients,acompromisedbarriercannotbecompletelyrepairedpossiblyduetothedeficiencyofbarrierrelatedproteinsresultingfromtheunderlyinggeneticdefect.InadditiontohigherskinsurfacepHandlowerstratumcorneumhydrationinwinter,defectivebarrieralonewillelevatethepHofthestratumcorneum,whichinturn,causesfurtherdelaysinbarrierrepair.Asustainedbarrierdefectprovokesexcesskeratinocyteproliferationandinflammation,initiatedinpartbytheproductionofepidermalcytokines,includingIL1,IL1,TNF,IL6,andIL8fromtheepidermis,leadingtoinflammatorycellinfiltrationandepidermalhyperplasia.
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YasuoKitajima ProfessorEmeritus,GifuUniversityGraduateSchoolofMedicine,Director,KizawaMemorialHospitalEducation: 19621968 M.D.,GifuUniversitySchoolofMedicine
19691973 Ph.D.,GifuUniversityGraduateSchool
(Biochemistry,MedicalScience)
ChronologyofEmploymentandAcademicAppointment: 19741975 PostgraduateResearchAssociate,DepartmentofBiochemistry,Gifu Univ.Sch.ofMed.
PostgraduateResearchAssociate,MembraneBiochemistry,DepartmentofBotany,UniversityofTexasatAustin,USA 19771981 Dermatologyresident.GifuUniv.Sch.ofMed. 19811983 AssistantProfessorofDermatology,GifuUniv.Sch.ofMed. 19831993 AssociateProfessorofDermatology,JichiMedicalSchool,Tochigi, 19931994 AssociateProfessorofDermatology,GifuUniv.Sch.ofMed. 19942009 ProfessorandChairman,DepartmentofDermatology,Gifu Univ.Sch.ofMed. 20022006 Director,GiguUniversityHospital 20092011 ActingDirector,KizawaMemorialHospital 2011preset Director,KizawaMemorialHospitalAward: 1986 MinamiPrize(JapaneseDermatologicalAssociation) 2000 PrizeofJapaneseSocietyforMedicalMycology 2007 ProfessorLuYanChinMemorialLectureship 2007 YasudaSakamotoMemorialAward(JapanOlearyMemorialFound) 20072012 AChairProfessorofKaohsiungMedicalUniversity 2008 GifuShinbunGreatAward(Science)fromGifuShibunNewsPaperCompany 2009,2011 SelectedoneofBestdoctorsinJapan 2009 CertificateofAppreciation,InternationalLeagueof DermatologicalSociety
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Society: JapaneseSocietyforInvestigativeDermatology(ChairmanofBoardofDirectors,19982002)JapaneseDermatologicalAssociation(BoardofCouncil,ViceChairmanofBoardofDirector20042006)JapaneseSocietyofMedicalMycology(BoardofCouncil,andDirectors)HonoraryMembershipfromKoreanSocietyforInvestigativeDermatology(2000)EditorialBoard: ArchivesofDermatology(19931997),(EditorialBoardasInternationalAdvisoryCommittee),JournalofDermatologicalScience(1993200,AssociateEditor), EpithelialCellBiology(19921997),JapaneseJournalofMedicalMycology(19871993)
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Implicationsofdesmosomeandcorneodesmosomeremodeling
dynamicsinpemphigusanddisordersofstratumcorneum
YasuoKitajima,MD,PhD
Prof.Emeritus,GifuUniversitySchoolofMedicine,Dermatology,KizawaMemorial
Hospital,MinokamoCity,Gifu,Japan
Desmosomesandcorneodesmosomesarethemostimportantadheringjunctionsto
providestrengthfortheepidermalsheetstructuremadeoflivingkeratinocytesand
enucleatedstratumcorneumcorneocytes,respectively.Thesejunctionsare
connecteddirectlywithtransmembranedesmosomalcadherins,desmogleins(Dsgs)
anddesmocollins(Dscs),mainlyDsg1/Dsc1andDsg3/Dsc3indesmosomesand
Dsg1/Dsc1withcorneodesmosinincorneodesmosomes.DsgsandDscsare
associatedwithseveralproteinsattheirinnercytoplasmicdomainstoanchorkeratin
intermediatefilaments.Desmosomesarenotstatic,butdynamicunitsthatundergo
regularremodelingtoallowforkeratinocyteoutwardmigrationintheepidermis.
Recently,twomutuallyreversibledesmosomaladhesionstateshavebeenrecognized,
i.e.,stablehyperadhesion(Ca2+independent)anddynamicweakadhesion
(Ca2+dependent).Theseconditionsaredynamicallychangedtoeachother
mediatedbyintracellularsignalingduringwoundhealing.Inaddition,aremarkable
impairmentofthisremodelingisobservedinpemphigusvulgaris(anautoimmune
blisteringdisease),causedbyantiDsg3antibodies,generatingaweakadhesion
desmosomestate.Thisdynamicnatureofdesmosomesislostbyfixingdesmosomal
cadherinswithcorneodesimosinatintercellulardomainofdesmosomesandwith
formationofpeptidebondsbyactivationoftransglutaminaseIatintracellarfaceof
desmosomes.Immediatelyafterformation,corneodesmosomesnormallycommitto
degradation,whichiscomplicatedlyregulatedbyproteolyticcleavageoftheir
respectiveextracellularportion(s),viakallikreinregulatedpeptidasesandcathepsins.
Thisproteolyticactivityisinturncontrolledbyavarietyofinhibitoryagents,
includingproteaseinhibitors,cholesterolsulfate,andanacidicgradient.The
impairmentofproteasecontrolcauseskeratinizationdisorders.Thisreviewfocuses
onthedynamicregulationofdesmosomesandcorneodesmosomesinrelationto
pemphigusanddisordersofstratumcorneum.
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Thisslideshowsthattheepidermiscanbedividedfunctionallyinto3layers.
Thefirstlayerisawaterbarrierformedbylamellarlipidsandasheetofcorneocytes,
rivetedwithcorneodesmosomes.
Thesecondlayerisamolecularbarrierformedbytightjunctionbetween
stratumcorneumandthesecondlayerofgranularcellsfromtheabove.Watercan
freelymovecrossingthetightjunctions.
Thethirdlayerisaprecursorsandsustaininglayerfortheabovetwolayers,
constructedwithakeratinocytesheetboundwithdesmosomesandkeratin
cytoskeletons.
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Scratchwoundingon6dayconfluentkeratinocyteculturesactivatesPKCalpha,
SrcandEGFR,causinganalterationofdesmosomesfromhyperadhesivetodynamic
lowaffinityconditions,sothatkeratinocytescouldmigrateoutfromthecolony.
Twostephypothesisofacantholysismechanisminpemphigusvulgaris:
GenerationofDynamic(lowaffinity)Ca2+sensitivedesmosomesandDsg3depletion.
Inculturedkeratinocytes,PVIgGactivatesproteinkinaseCandEGFR,whichalterthe
Ca2+independenthyperadhesivedesmosometoCa2+sensitivedynamic
desmosomesorevenweakenstheadhesivestrength,leadingkeratinocytesto
becomemoresensitivetocellularmechanismsforblisteringprocesses,i.e.,
nonassemblyanddepletionofDsg3indesmosomes.
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TheupperpartofSCshowsabasketweavepattern,wherecorneodesmosomesare
distributedattheperipheryofcorneosomes.Thedeepersamplesbytapestripping
ofstratumcorneumillustrateahomogeneouslyspottedpatternovertheentire
corneocytesurface(s)asyoucanseehere,thisindicatesthatcorneodesmosomes
reducethenumberfromthedeepertotheupperasyoucanseehere.Therightend
ofslideshowsschematicallythatdegradationofcorneodesmosomesisacomplicated
processthatisfinelyregulatedbyproteolyticcleavageoftheextracellulardomains
withkallikreinregulatedpeptidases(KLKs)andotherproteases(rightschema).This
proteolyticactivityisinturncontrolledbyavarietyofinhibitoryagents,including
proteaseinhibitorsassuchLEKTI,cholesterolsulfate,andanacidicgradient.
Consequently,thenumberofcorneodesmosomesgraduallydecreasesfromthe
deepertothesuperficialSC,andtheirdistributionwhichcoversthewholesurfaceof
corneocytesinthedeeperSCbecomeslimitedtoonlytheperipheryofindividual
corneocytesinthesuperficialSC,formingahoneycombpatterndistribution.
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Thisslideshowshistopathologyanddistributionofcorneodesmosomesin
corneocyteswithincreasedcholesterolsulfate.HistopathologyshowsamoderatedegreeofhyperkeratosiswithcompactSCthatlacksthebasketweavepatternofnormalSC,andwitheitheranormalorthickenedgranularcelllayer.Corneodesmosomesshowahomogenousdottednonperipheraldistribution,becauseofKLKinhibitionbycholesterolsulfate,whichisincreasedduetomutationofcholesterolsulfataseresultingininsufficientenzymaticactivity. Thelossofnormalhoneycombpatternofcorneodesmosomes(CDS)maybeprofoundlyinvolved.Whentheskinisgettinglateralpullingforcesorpressures,theCDShoneycombpatternmaypermittheskintoattenuatesuchforces/pressuresbyallowingthestretchorshrinkageofcorneocyteshapebyslidingofthecentralpartbetweentheupperandlowerSCsinsyncwiththemultilayeredlipidsbetweencorneocytes.ThisallowstheSCtobend/flexwithoutcrackinginnormalepidermalSC.Incontrast,amoregeneralizeddistributionofCDSwouldnotallowforsimilarbending/flexibility,asthewholesurfaceofcorneocyteswouldbefixedtoeachotherviarivetsofCDS;assuch,thecracksintheSCmaybegeneratedtoadjusttothebendingforcesandpressuresinthepatientskinSC.
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AkiharuKubo
AssistantProfessor DepartmentofDermatology,KeioUniversitySchoolofMedicine,JapanEducationalDetails: OsakaUniversity,Japan,19871994 OsakaUniversityHospital,Japan,19941995,InternshipinDermatology OsakaRosaiHospital,Japan,19951996,InternshipinDermatology DepartmentofDermatology,OsakaUniversity,Japan,19962000,Ph.D. Certifications: M.D.,1994 Ph.D.,OsakaUniversity,2000 DermatologySpecialistinJapan,2008 GeneticDiseaseSpecialistinJapan,2013Awards 2010SeigoMinamiMemorialAwardofJapaneseDermatologicalAssociation 2010JSID'sFellowshipSHISEIDOAward 2011YoungResearcherAwardof12thInternationalWorkshoponLangerhansCellsExperienceinResearch: 19891991:DepartmentofPharmacolgyII,FacultyofMedicine,OsakaUniversity 19962001:ERATOTsukitaCellAxisProject 20012006:DepartmentofCellBiology,FacultyofMedicine,KyotoUniversity 2006 :DepartmentofDermatology,SchoolofMedicine,KeioUniversityPublications:KuboA,NagaoK,YokouchiM,SasakiH,andAmagaiM.ExternalantigenuptakebyLangerhanscellswithreorganizationofepidermaltightjunctionbarriers.J.Exp.Med.206:29372946,2009.KawasakiH,NagaoK,KuboA,HataT,ShimizuA,MizunoH,YamadaT,andAmagaiM.Alteredstratumcorneumbarrierandenhancedpercutaneousimmuneresponsesinfilaggrinnullmice.JAllergyClinImmunol.129:15381546.e6,2012.Kubo A, Nagao K, Amagai M. Epidermal barrier dysfunction and cutaneoussensitizationinatopicdiseases.JClinInvest122:440447,2012.KuboA,IshizakiI,KuboA,KawasakiH,NagaoK,OhashiYetal.Thestratumcorneumcomprises three layerswith distinctmetalion barrier properties. Sci Rep. 3:1731,2013.Yoshida K, Yokouchi M, Nagao K, Ishii K, Amagai M, *Kubo A. Functional tightjunctionbarrier localizes in the second layerof the stratumgranulosumofhumanepidermis.JDermatolSci71,8999,2013.
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KuboA,ShiohamaA,SasakiT,NakabayashiK,KawasakiH,AtsugiT,SatoS,ShimizuA,MikamiS,TanizakiH,UchiyamaM,MaedaT, ItoT,Sakabe J,HeikeT,OkuyamaT,Kosaki R, Kosaki K, Kudoh J, Hata K, Umezawa A, Tokura Y, Ishiko A, Niizeki H,KabashimaK,MitsuhashiY,AmagaiM.MutationsinSERPINB7,EncodingaMemberof the Serine Protease Inhibitor Superfamily, CauseNagashimatype PalmoplantarKeratosis.AmJHumGenet.93,945956,2013.YoshidaK,KuboA,FujitaH,YokouchiM, IshiiK,KawasakiH,NomuraT,ShimizuH,KouyamaK,EbiharaT,NagaoK,AmagaiM.DistinctbehaviorofhumanLangerhanscells and inflammatory dendritic epidermal cells at tight junctions in atopicdermatitis.JAllergyClinImmunol. 134:85664,2014.
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Tightjunctionbarriersintheskinandskindiseases
AkiharuKubo,M.D.,Ph.D.
DepartmentofDermatology,KeioUniversitySchoolofMedicine,Japan
Livingorganismsrelycriticallyonsurfacebarrierstoisolatethemselvesfromthe
externalenvironmentandtomaintainhomeostasis.Inthemammalianskin,the
outersurfaceofthebodyiscoveredbyastratifiedepithelialcellularsheetcalledthe
epidermis.Theepidermishastwosetsofphysicalbarriers,thestratumcorneum(SC)
andtightjunctions(TJs).Thesetwobarrierspreventtheoutsideinpenetrationof
externalantigensortheinsideoutleakageofinternalconstituents.TheSC,whichis
composedofterminallydifferentiatedcornifiedcells(corneocytes)and
intercorneocytelipids,servesasanairliquidinterfacebarriertoprotecttheviable
celllayerunderneath.UndertheSC,stratumgranulosum(SG)cellsformtheouter
layersofviablestratifiedkeratinocytes.WhenuppermostthreeSGlayersarenamed
SG1,SG2,andSG3fromthesurfacetotheinward,TJssealtheintercellularspacesof
theSG2cellsandlimitthemovementofwatersolublemoleculesthrough
paracellularpathway.
Filaggrindeficiencypredisposepatientstoatopicdermatitis(AD)byimpairment
ofstratumcorneum(SC)barrierfunction,whichmayfacilitatepercutaneous
sensitization.InthisimpairedSCbarriermodelofAD,theexternalantigensthat
arefacilitatedtopenetratethroughtheSCarespeculatedtobetakenupbyskin
dendriticcellsforantigenpresentationtotheimmunesystem.Externalwatersoluble
antigensareconsideredtobeheldoutsideTJbarrierandtakenupbyepidermal
Langerhanscells(LCs)viatheinsideoutTJpenetrationofLCdendritesforantigen
presentationtoTcells.OnceTJbarrierisabrogated,theseexternalantigensare
readytopenetrateintothedermis,wheretheywillbetakenupbydermaldendritic
cells.Therefore,theimpairedepidermalTJfunctionisconsideredtoaffectthemode
ofimmunereactionwithdistinctpopulationofdendriticcellsthattakeupexternal
antigens.Inthistalk,wewilldiscussthecrosstalkbetweentheSCandtheTJbarriers
andapossibleviciouscyclebetweenskinbarrierdeficienciesandskininflammation
inchronicdermatitis,especiallyinAD.
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Figure1Theskinsbarrierfunctionhasthreeelements:thestratumcorneum(airliquidbarrier),tightjunctions(TJs:liquidliquidbarrier),andtheepidermalLangerhanscell(LC)network(immunologicalbarrier). ExternalwatersolubleantigensareconsideredtobeheldoutsideTJbarrierandtakenupbyLCsviatheinsideoutTJpenetrationofLCdendritesuponactivation.
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Figure2WefoundthatLangerhanscells(LCs),butnotinflammatorydendriticepidermalcells(IDECs),extendtheirdendritesthroughthetightjunction(TJ)probablytocaptureantigensfromoutsidetheTJbarrierintheerythematouslesionalskinofatopicdermatitis(AD). LangerinwasaccumulatedatthetipoftheTJpenetrateddendrites,whileFcRIwasexpressedbelowTJsbybothLCsandIDECs,possiblytocapturepenetratedantigens. ThebehavioraldifferencesbetweenthetwotypesofdendriticcellsfoundintheskinofADprovideanimportantframeworktodissectthepathophysiologyofAD.
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JiaYouFang,Ph.D
Address:261WenHwa1stRoad,Kweishan,Taoyuan333,
Taiwan
Phone:88632118999ext5715
Fax:88632118236
Email: [email protected]
Current status:Dean,CollegeofHumanEcology,ChangGungUniversityofScience
andTechnology,Taiwan
Graduate from: Ph.D, Graduate Institute of Pharmaceutical Sciences, Kaohsiung
MedicalCollege,Taiwan
Research Interests: Nanomedicine; Pharmaceutics; Pharmacokinetics; Cosmetic
science
EditorialBoard:
RecentPatentsinDrugDeliveryandFormulation
JournalofBiomedicalNanotechnology
Toxins
CurrentNanoscience
JournalofDrugDelivery
-
Strategyandapplicationoftopical/transdermaldrugdelivery
enhancedbylaser
JiaYouFangCollegeofHumanEcology,ChangGungUniversityofScienceandTechnology,Taoyuan,TaiwanAbstractUsinglaserscanbeaneffectivedrugpermeationenhancementapproachforfacilitatingdrugdeliveryintooracrosstheskin.Thecontrolleddisruptionandablationofthestratumcorneum(SC),thepredominantbarrierfordrugdelivery,isachievedbytheuseoflasers.Thepossiblemechanismsoflaserassisteddrugpermeationarethedirectablationoftheskinbarrier,opticalbreakdownbyaphotomechanicalwave(PW),andaphotothermaleffect.Ithasbeendemonstratedthatablativeapproachesforenhancingdrugtransportprovidesomeadvantages,includingincreasedbioavailability,fasttreatmenttime,quickrecoveryofSCintegrity,andthefactthatskinsurfacecontactisnotneeded.Inrecentyears,theconceptofusinglasertechniquestotreattheskinhasattractedincreasingattention.Iwilldescriberecentdevelopmentsusingnonablativeandablativelasersfordrugabsorptionenhancement.Thisspeechsystematicallyintroducestheconceptsandenhancementmechanismsoflasers,highlightingthepotentialofthistechniqueforgreatlyincreasingdrugabsorptionviatheskin.Laserswithdifferentwavelengthsandtypesareemployedtoincreasedrugpermeation.Theseincludetherubylaser,theerbium:yttriumgalliumgarnet(Er:YAG)laser,theNd:YAGlaser,theCO2laser,andthefractionallaser.Thelasermodalityisusefultoenhancethepermeationofawidevarietyofpermeants,suchassmallmoleculedrugs,macromolecules,andnanoparticles.Thispotentialuseofthelaseraffordsanewtreatmentfortopical/transdermalapplicationwithsignificantefficacy.Furtherstudiesusingalargegroupforhumansorpatientsareneededtoconfirmandclarifythefindingsinanimalstudies.Althoughthelaserfluenceoroutputenergyusedforenhancingdrugabsorptionismuchlowerthanfortreatmentofskindisordersandrejuvenation,thesafetyofusinglasersisstillanissue.Cautionshouldbeusedinoptimizingthefeasibleconditionsofthelasersinbalancingtheeffectivenessofpermeationenhancementandskindamage.
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MitsuhiroDenda
Name: MitsuhiroDenda Position: ExpertScientist,ShiseidoResearchCenterPlaceofbirth:Kobeshi,HyogoPrefecture,JapanDateofbirth: August23,1960,Nationality: JapaneseEducation: EnteredFacultyofEngineering,KyotoUniversity,April,1979,andgraduatedMarch,1983,withthedegreeofBachelorofEngineering. ObtainedanM.S.(MasterofEngineering)fromKyotoUniversity,March,1985 ReceivedaPh.D.(DoctorofEngineering,NO.14520)inJuly,1994fromKyotoUniversityforathesisentitled:Physicochemicalfeaturesofhumanskinstratumcorneum.Occupation: ResearcherofCoreResearchforEvolutionalScienceandTechnology,JapanScienceandTechnologyAgency(20102016)ExpertScientist,ShiseidoResearchCenter(2009todate). SeniorScientist,ShiseidoResearchCenter(2002to2008)Visitingresearcher,DermatologySection,UniversityofCalifornia,SanFrancisco,underthedirectionofProf.P.M.EliasandProf.K.R.Feingold(1993to1996)Review(English)1.Skinbarrierfunctionasaselforganizingsystem.DendaM.Forma15(2000)227232
2.Influenceofdryenvironmentonepidermalfunction.DendaM.JDermatolSci24(2000)
Suppl.1S22S28
3.Newstrategiestoimprovebarrierfunction.DendaM.AdvDrugDelivRev54(Suppl.1)
S123S130,2002
4.Ions,electricpotentialandbarrierfunction.DendaM.TheJournalofSkinBarrierResearch
4:1319,2002
5.Epidermalkeratinocytesastheforefrontofthesensorysystem.DendaM.,NakataniM.,
IkeyamaK.,TsutsumiM.,DendaS.ExpDermatol16:157161,2007
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6.Epidermalkeratinocytesastheinterfaceofbodyandenvironment.DendaM.TheJournal
ofSkinBarrierResearch8:36,2008
7.Methodologytoimproveepidermalbarrierhomeostasis:Howtoacceleratethebarrier
recovery?DendaM.InternationalJournalofCosmeticScience31:7986,2009
8.Sensorysystemsofepidermalkeratinocytes.DendaM.TheJournalofSkinBarrier
Research15:2434,2013
OriginalPaper(English)(Correspondingauthor)20082014:1.DendaM.andFuziwaraS.Visibleradiationaffectsepidermalpermeabilitybarrierrecovery:
Selectiveeffectsofredandbluelight.JInvestDermatol128:13356,2008.
2.KawaiE,NakanishiJ,KumazawaN,OzawaK,DendaM*.Skinsurfaceelectricpotentialas
anindicatorofskincondition:Anew,noninvasivemethodtoevaluateepidermalcondition.
ExpDermatol17:688692,2008
3.KatsutaY,IidaT,HasegawaK,InomataSandDendaM.Functionofoleicacidonepidermal
barrierandcalciuminfluxintokeratinocytesisassociatedwithNMDAtypeglutamate
receptor.BrJDermatol160:6974,2009
4.TsutsumiM,DendaS,InoueK,IkeyamaK,DendaM*.Calciumiongradientsanddynamics
inculturedskinslicesofrathindpawinresponsetostimulationwithATP.JInvestDermatol
129:584589,2009
5.TsutsumiM.,IkeyamaK.,DendaS.,NakanishiJ,FuziwaraS.,AokiH.,DendaM*.
Expressionsofrodandconephotoreceptorlikeproteinsinhumanepidermis.ExpDermatol
18:567570,2009
6.TsutusmiM.,InoueK.,DendaS.,Ikeyama,K.,GotoM.,DendaM*.
Mechanicalstimulationevokedcalciumwavesinproliferatinganddifferentiatedhuman
keratinocytes.CellTissueRes338:99106,2009
7.TsutsumiM,KitahataH,NakataS,SannoY,NagayamaM,andDendaM*.Mathematical
analysisofintercellularcalciumpropagationinducedbyATPSkinResTechnology2010;16:
146150
8.DendaMandNakataniM.Accelerationofpermeabilitybarrierrecoverybyexposureof
skinto1030kilohertzsound.BrJDermatol2010;162:503507
9.IkeyamaK,DendaS,TsutsumiM,DendaM.Neuronalnitricoxidesynthaseinepidermisis
involvedincutaneouscirculatoryresponsetomechanicalstimulation.JInvestDermatol
130:11581166,2010
10.DendaMandKumazawaN.Effectsofmetalsonskinpermeabilitybarrierrecovery.Exp
Dermatol19:e124e127,2010
11.DendaS.,DendaM.,InoueK.,HibinoT.Glycolicacidinduceskeratinocyteproliferationin
askinequivalentmodelviaTRPV1activation.JDermatolSci57:108113,2010
12.DendaM.,TsutsumiM.,GotoM.,IkeyamaK.,DendaS.TopicalapplicationofTRPA1
agonistsandbriefcoldexposureaccelerateskinpermeabilitybarrierrecovery.JInvest
-
Dermatol130:19421945,2010
13.TsutsumiM.,DendaS.,IkeyamaK.,GotoM.,DendaM*.Exposuretolowtemperature
induceselevationofintracellularcalciuminculturedhumankeratinocytes.JInvestDermatol
130:19451948,2010
14.GotoM.IkeyamaK.,TsutsumiM,DendaS,DendaM.CalciumIonPropagationinCultured
KeratinocytesandOtherCellsinSkininResponsetoHydraulicPressureStimulation.JCell
Physiol224:229233,2010
15..IkeyamaKandDendaM.Effectofendothelialnitricoxidesynthaseonepidermal
permeabilitybarrierrecoveryafterdisruption.BrJDermatol163:915919,2010
16.DendaM,TsutsumiM,DendaS.TopicalapplicationofTRPM8agonistsacceleratesskin
permeabilitybarrierrecoveryandreducesepidermalproliferationinducedbybarrierinsult:
TheroleofcoldsensitiveTRPreceptorsinepidermalpermeabilitybarrierhomeostasis.Exp
Dermatol19:791795,2010
17.NakataniM,KawasoeT,DendaM.Sexdifferenceinhumanfingertiprecognitionof
micronlevelrandomnessasunpleasant.InternationalJournalofCosmeticScience
33:346350,2011
18.NakataS,IkeguchiA,ShiotaT,KomoriR,KumazawaN,TsutsumiM,DendaM.Interactions
betweenSexHormonesanda1,2diOmyristoylsnglycero3phosphocholineMolecular
Layer:CharacteristicsoftheLiposome,SurfaceAreaversusSurfacePressureofthe
Monolayer,andMicroscopicObservation.BullChemSocJapan84:283289,2011
19.GotoM,IkeyamaK,TsutsumiM,DendaS,DendaM.Phosphodiesteraseinhibitorsblock
theaccelerationofskinpermeabilitybarrierrepairbyredlight.ExpDermatol20:568571,
2011
20.TsutsumiM,GotoM,DendaS.DendaM.Morphologicalandfunctionaldifferencesin
coculturesystemofkeratinocytesanddorsalrootganglionderivedcellsdependingontime
ofseeding.ExpDermatol20:464467,2011
21.KawaiE.,KumazawaN,OzawaK,DendaM.Skinsurfaceelectricalpotentialasan
indicatorofskincondition:Observationofsurfactantinduceddryskinandmiddleagedskin.
ExpDermatol20:757759,2011
22.TsutsumiM,KumamotoJ.DendaM.Intracellularcalciumresponsetohightemperatureis
similarinundifferentiatedanddifferentiatedculturedhumankeratinocytes.ExpDermatol20:
839840,2011
23.DendaM.Effectsoftopicalapplicationofaqueoussolutionsofhexosesonepidermal
permeabilitybarrierrecoveryrateafterbarrierdisruption.ExpDermatol20:943944,2011
24.DendaS,KumamotoJ,TakeiK,TsutsumiM,AokiH,DendaM.Ryanodinereceptorsare
expressedinepidermalkeratinocytesandassociatedwithkeratinocytedifferentiationand
epidermalpermeabilitybarrierhomeostasis.JInvestDermatol132:6975,2012
25.Denda,S,TakeiK,KumamotoJ,Goto,M,Tsutsumi,M,Denda,M.Oxytocinisexpressedin
-
epidermalkeratinocytesandreleaseduponstimulationwithadenosine
5[gammathio]triphosphateinvitro.ExpDermatol21:535537,2012
26.NakataS,ShiotaT,KumazawaN,DendaM.Interactionbetweenamonosaccharideanda
phospholipidmolecularlayer.ColloidsandSurfacesA:PhysicochemicalandEngineering
Aspects.405:1418,2012
27.TsutsumiM,NakataniM,KumamotoJ,DendaS,Denda,M.Invitroformationof
organizedstructurebetweenkeratinocytesanddorsalrootganglioncells.ExpDermatol
21:886888,2012
28.FeingoldKR,DendaM.Regulationofpermeabilitybarrierhomeostasis..ClinDermatol.
201230:2638.
29.DendaM,TakeiK,DendaS.Howdoesepidermalpathologyinteractwithmentalstate?
MedicalHypothesis.80:194196,2013
30.IkeyamaK,NakataniM,KumamotoJ,DendaM.Distinctintracellularcalciumresponsesof
individualculturedhumankeratinocytestoairpressurechanges.SkinResTech19:346351,
2013
31.TsutsumiM,GotoM,DendaM.Dynamicsofintracellularcalciuminculturedhuman
keratinocytesafterlocalizedcelldamage.ExpDermatol22:367369,2013
32.KumamotoJ,GotoM,DendaS,NakataniM,TakasugiY,TsuchiyaK,SimizuY,TakatsuruY,
DendaM.Externalnegativeelectricpotentialacceleratesexocytosisoflamellarbodiesin
humanskinexvivo.ExpDermatol22:421413,2013
33.TakeiK,DendaS,KumamotoJ,DendaM.Lowenvironmentalhumidityinducessynthesis
andreleaseofcortisolinanepidermalorganotypicculturesystem.ExpDermatol22:662664,
2013
34.KumamotoJ,NakataniM,TsutsumiM,GotoM,DendaS,TakeiK,DendaM.Coculture
systemofkeratinocytesanddorsalrootganglionderivedcellsforscreeningneurotrophic
factorsinvolvedinguidanceofneuronalaxongrowthintheskin.ExpDermatol23:5860,
2014
35.DendaM,DendaS,TsutsumiM,GotoM,KumamotoJ,NakataniM,TakeiK,KitahataH,
NakataS,SawabuY,KobayashiY,NagayamaM.Frontiersinepidermalbarrierhomeostasis
anapproachtomathematicalmodelingofepidermalcalciumdynamics.ExpDermatol
23:7982,2014
36.DendaM,TsutsumiM.Possibleroleofepidermalkeratinocytesintheconstructionof
acupuncturemeridians.JournalofAcupunctureandMeridianStudies7:9294,2014
37.KobayashiY,SannoY,SakaiA,SawabuY,TustsumiM,GotoM,KtahataH,NakataS,
KumamotoJ,DendaM,NagayamaM.MathematicalModelingofCalciumWavesInducedby
MechanicalStimulationinKeratinocytes.PLOSONE9:e92650,2014
38.DendaM.Newlydiscoveredolfactoryreceptorsinepidermalkeratinocytesareassociated
withproliferation,migrationandreepithelializationofkeratinocytes.JInvestDermatol134:
-
26772679,2014
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EpidermisastheThirdBrain?
MitsuhiroDenda
Therolesofthebrainarereceptionofenvironmentalinformationfromsensory
organs,informationprocessingandtransmissionofinformationtothesystemsofthe
wholebody.However,thedigestiveorganshaveanindependentnervesystem,which
hasbeencalledthesecondbrain.Weproposethattheepidermis,whichformsthe
interfacebetweenthebodyandtheenvironment,couldbeconsideredasathird
brain,becauseitcontainsenvironmentalsensorsandasensory
informationprocessingsystem,anditgeneratesavarietyofhormonesand
neurotransmittersthatinfluencewholebodystatesandemotions.Specifically,
epidermalkeratinocytescontainsensorsofmechanicalstress,temperatureand
chemicalstimuli.Further,wehaveshownthataseriesofneurotransmitterreceptors,
whichplaycrucialrolesinthecentralnervoussystemandbrain,arefunctionally
expressedinkeratinocytes.Culturedhumankeratinocytescangeneratestructures
similartothoseseeninthebrain.Moreover,allthecomponentsofthe
hypothalamopituitaryadrenal(HPA)axisappeartobepresentinepidermal
keratinocytes.Overall,theseresultssuggestthatepidermishasanimportantrolein
adaptingwholebodyphysiology,andprobablyalsoemotionalresponse,tochanging
environments.
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YutakaHatanoCurrentPosition:AssociateProfessor Department:DepartmentofDermatology Organization:FacultyofMedicine,OitaUniversity Education1992(Mar) M.D. FacultyofMedicine,OitaMedicalUniversity2001(Mar) Ph.D. GraduateSchoolofMedicine,OitaMedicalUniversityProfessionalExperience2001(Jun) ResearchAssociate,OitaMedicalUniversity2006(Jan)2007(Dec)Post.Doc.Fellow,DermatologyServices,VeteransAffairsMedicalCenter,DepartmentsofDermatology,UniversityofCalifornia,SanFrancisco2008(Oct) AssistantProfessor,FacultyofMedicine,OitaUniversity2014(Apr) AssociateProfessor,FacultyofMedicine,OitaUniversity ProfessionalSocietyJapaneseDermatologicalAssociationTheJapaneseSocietyforInvestigativeDermatology(Council)JapaneseSocietyofAllergologyTheJapaneseSocietyforDermatoallergologyandContactDermatitisPanAsianPacificSkinBarrierResearchSociety
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Whydopatientswithatopicdermatitisexhibitpredisposition
toatopicdermatitis?possiblepathwaysfrombarrierrelated
geneabnormalitiesintoemergenceofatopicdermatitis
YutakaHatano
Abstract:Permeabilitybarrierdysfunctionisakeymechanisticfeatureinthe
pathogenesisofatopicdermatitis(AD)andhasbeenknowntobecausedeither
geneticallyorsecondarily.Avarietyofmechanismsshouldbeinvolvedinthe
pathwayfromabnormalitiesofbarrierrelatedmoleculesintoinductionor
exacerbationofallergicinflammation.Iwouldliketoproposenotwellknownbut
possiblemechanismsbywhichpatientswithabnormalitiesofbarrierrelated
moleculesexhibitapredispositiontoAD.Wefoundthatexpressionsof
proinflammatorycytokinesinkeratinocytescouldbemodifiedbyreductionof
permeabilitybarrierrelatedgenes,suchasfilaggrinandloricrin.Inaddition,we
demonstratedusingflakytailmicethatdisturbedmaintenanceofstratumcorneum
aciditycouldberegardedasamissinglinktoconnectbetweenpermeability
barrierrelatedgeneabnormalitiesandenvironmentalfactorsinthepathogenesisof
AD.
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YoshikazuUchidaPosition: ResearchScientist(Dermatology) Address:DermatologyService(190),VeteransAdministrationMedicalCenter,1700OwensStreet,Room326,SanFrancisco,CA94158Tel:(415)5750524,Fax: (415)7502106Email:[email protected] TokyoCollegeofPharmacy, Tokyo, Japan B.A. Pharmacy1984 TokyoCollegeofPharmacy, Tokyo, Japan M.S. Pharmacy1991 TokyoCollegeofPharmacy,Tokyo,Japan Ph.D. PharmacyEMPLOYMENTPRINCIPALPOSITIONSHELD:198497 CosmeticsLaboratory,KaneboLtd. ResearchScientist
199697 CosmeticsLaboratory,KaneboLtd. SeniorResearchScientist199799 BasicResearchLaboratory,KaneboLtd. SeniorResearchScientist199903 UniversityofCalifornia,SanFrancisco
Dermatology
AssistantResearchBiochemist
2003132013
UniversityofCalifornia,SanFrancisco
Dermatology
UniversityofCalifornia,SanFrancisco
AssociateResearchDermatologistResearchDermatologist
present Dermatology OTHERPOSITIONSHELDCONCURRENTLY:198587 UniversityofTokyo
Biochemistry
ResearchFellow
198889 TokaiUniversity
Biochemistry
ResearchFellow
199294199698
UniversityofCalifornia,SanFrancisco
Dermatology
UniversityofCalifornia,SanFrancisco
PostdoctoralResearchFellowPostdoctoralResearchFellow
Dermatology
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RESEARCHAREA:
For20plus years,Dr.Uchidahas investigated themolecular structures,metabolic
pathwaysandregulationof sphingolipids;inparticular,epidermal sphingolipids,in
relation toproliferation/differentiation, stressinducedapoptosis,epidermalbarrier
function, and skin disease. His extensive knowledge of analytical chemistry,
(molecular)biochemistry, and cutaneous biology fields allowed him to recently
characterize a novel transcriptional regulatory mechanism of external
stressmediatedcathelicidinantimicrobialpeptide(CAMP/LL37) (J.BiolChem,2011)
and to further elucidate that sphingosine1phospate signaling is involved in
upstreamsignalofthismechanism (MolCellBioland J InvestDermatol,2013),and
to characterize another sphingolipid signaling (via ceramide1phosphate)
dependentpathwayofhumanbetadefensinsynthesis(willbeacceptedafterminor
revision [Mol Cell Biol]).Moreover, inhis tenure asaSenior Scientist at theBasic
Research and Cosmetics Laboratory, Kanebo Ltd., he also gained experience
developing topical formulations containing GRAS ingredients or drugrelated
compoundsforinflammatoryskindisease,acnes,woundhealing,andagedskin.ExperienceandProfessionalMemberships1982present TheJapaneseBiochemicalSociety
1986present JapaneseConferenceonBiochemistryofLipids
1992present SocietyforInvestigativeDermatology
1995present JapaneseSocietyforInvestigativeDermatology
1998present AmericanAssociationfortheAdvancementofScience
2008present ExternalReviewBoard,TheSocietyofJapaneseWomenScientist
Honor2006 KeimeiLifeScienceAward(KeimeiFoundation,Japan)
2007 BestBasicPosterPresentationatthe68thAnnualMeetingoftheSocietyfor
InvestigativeDermatology
PUBLICATIONS:PEERREVIEWEDORIGINALPUBLICATIONS(PAST3YRS,SELECTEDFROMTOTAL80)1.BikleDD,TeichertA,ArnoldLA,UchidaY,EliasPM,OdaY.Differentialregulationof
epidermalfunctionbyVDRcoactivators.J.SteroidBiochem.Mol.Biol.121:30813,2010
2.GlennD.J.,WangF.,NishimotoM.,CruzM.C.,UchidaY.,HolleranW.M.,ZhangY.,
YeghiazariansY.,GardnerD.G.AMurineModelofIsolatedCardiacSteatosisLeadsto
-
Cardiomyopathy.Hypertension57:21622,2011
3.AburaiK.,YoshinoS.,SakaiK.,SakaiH.,AbeM.,LoiseauN.,HolleranW.M.,UchidaY.,
SakamotoK.PhysicochemicalAnalysisofLiposomeMembranesConsistingofModelLipidsin
theStratumCorneum.J.OleoSci.60:197202,2011
4.NakajimaK.,UchidaY.,AkiyamaM.,MoritaY.ShimizuH.,SanoS.Alteredlipidprofilesin
thestratumcorneumofSjogrenLarssonsyndrome.J.Dermatol.Sci.,63:646,2011
5.KimH.,KimJ.,ParkJ.,KimS.H.,UchidaY.,HolleranW.M.,ChoY.WaterExtractofGromwell
(Lithospermumerythrorhizon)EnhancesWoundHealingviaIncreasedMigrationofHuman
KeratinocytesanddermalFibroblastswithIncreasedLipidSynthesis.SkinPharmacol.&
Physiol.25:5764,2011
6.ParkK,EliasP.M.,OdaY.,MackenzieD.,MauroT.,HolleranW.M.,UchidaY.Regulationof
CathelicidinExpressionByanERStressSignaling,VitaminDReceptorIndependentPathway.
J.Biol.Chem.,286:34121130,2011
7.CelliA.,MackenzieD.S.,ZhaiY.,TuC.L.,BikleD.D.,HolleranW.M.,UchidaY.,Mauro
T.M.SERCA2controlledCa(2)+dependentkeratinocyteadhesionanddifferentiationis
mediatedviathesphingolipidpathway:atherapeutictargetforDarier'sdisease.J.Invest.
Dermatol.132:118895,2012
8.Lin,T.K.,CrumrineD.,AckermanL.D.,SantiagoJ.L.,RoelandtT.,UchidaY.,HupeM.,Fabrias,
J.G.,AbadL.,RiceR.H.,EliasP.M.CellularChangesthatAccompanySheddingofHuman
Corneocytes.J.Invest.Dermatol.132:24302439,2012
9.Tarutani,M.,NakajimaK.,UchidaY.,TakaishiM.,GotoInoueN.,IkawaM.,SetouM.,
KinoshitaT.,EliasP.M.,SanoS.,MaedaY.GPHRDependentFunctionsoftheGolgiApparatus
AreEssentialfortheFormationofLamellarGranulesandtheSkinBarrier.J.Invest.
Dermatol.132:201925,2012
10.GotoInoueN.,TakahiroT.,ZaimaN.,NakajimaK.,HolleranW.M.,SanoS.,UchidaY.*,
SetouS.*(*contributedequallytothisworkascoseniorauthor).Imagingmass
spectrometryvisualizeceramidesandthepathogenesisofDorfmanChanarinsyndromedue
toceramidemetabolicabnormalityinskin.e49519,2012
11.JiangY.J.,KimP.,UchidaY.,EliasP.M.,BikleD.D.,GrunfeldC.,FeingoldK.R.,Ceramides
stimulatecaspase14expressioninhumankeratinocytes.ExpDermatol22:1138,2013
12.BorkowskiA.W.,ParkK.,UchidaY.,GalloR.L.ActivationofTLR3inKeratinocytesIncreases
ExpressionofGenesInvolvedinFormationoftheEpidermis,LipidAccumulationand
EpidermalOrganelles.J.Invest.Dermatol.133:203140,2013
13.ParkK,EliasP.M.,HupeM.,BorkowskiA.W.,GalloR.L.,ShinK.O.,LeeY.M.,HolleranW.M.,
EliasP.M.,UchidaY.Resveratrolstimulatessphingosine1phosphatesignalingofcathelicidin
production.J.Invest.Dermatol.133:19429,2013
14.YoumJ.K.,ParkK.,UchidaY.,ChanM.,MauroT.M.,HolleranW.M.,EliasP.M.Local
blockadeofglucocorticoidactivationreversesstressandglucocorticoidinduceddelaysin
-
cutaneouswoundhealing.WoundRepairRegen21:71522,2013
15.LoiseauN.,ObataY.,MoradianS.,SanoH.,YoshinoS.,AburaiK.,TakayamaK.,Sakamoto
K.,HolleranW.M.,EliasP.M.,UchidaY.Alteredsphingoidbaseprofilespredictcompromised
membranestructureand permeabilityinatopicdermatitis,J.Dermatol.Sci.72:29603,
2013
16.ParkK.,JuW.C.,YeoJ.H.,KimJ.Y.,SeoH.S.,UchidaY.,ChoY.IncreasedOPG/RANKLratioin
conditionedmediumofsoybeantreatedosteoblastsinfluencestosuppressRANKLinduced
osteoclastdifferentiation.Int.J.Mol.Med33:17884,2013
17.ParkK.,KimY.I.,ShinK.O.,SeoH.S.,KimJ.Y.,MannT.,OdaY.,LeeY.M.,HolleranW.M.,
EliasP.M.,UchidaY.Thedietaryingredient,genistein,stimulatescathelicidinantimicrobial
peptideexpressionthroughanovelS1Pdependentmechanism.JNutrBiochem.25:73440,
2014
18.Sun,R.,A.Celli,D.Crumrine,M.Hupe,L.C.Adame,S.D.Pennypacker,K.Park,Y.Uchida,
K.R.Feingold,EliasP.M.,Llic,D.,andT.M.Mauro,LoweredHumidityProducesHuman
EpidermalEquivalentswithEnhancedBarrierProperties.TissueEngPartCMethods:2014(in
press)
19.Tiganescu,A.,HupeM.,UchidaY.,Mauro,T.,P.M.Elias,andW.M.Holleran,Increased
glucocorticoidactivationduringmouseskinwoundhealing.JEndocrinol.221:5161,2014.
PEERREVIEWEDREVIEWARTICLES(TOTAL5):1.HolleranW.M.,TakagiY.,UchidaY.Epidermalsphingolipids:Metabolism,function,and
role(s)inskindisorders.FEBSLetters580:54565466,2006
2.UchidaY.,HolleranW.M.OmegaOacylceramide,alipidessentialformammaliansurvival.
J.DermatolSci51:7787,2008
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TheSignalingRoleofCeramideandItsMetabolitesin
CutaneousAntimicrobialDefense
YoshikazuUchida,Ph.D.
Skinepidermisdeploysmultiplebarriers;i.e.,permeability,mechanicalstress,oxidativestress/UVlightandantimicrobial.Priorstudiesdemonstratedthatdiversetypesofexternalperturbations,suchasepidermalpermeabilitydisruption,oxidative/UVirradiation,andwounding(allwhichincreasetheriskofmicrobialpathogeninvasionandcolonization,aswellasmicrobialinfection),simulateepidermalantimicrobialpeptide(AMP)production,includingproductionoftwokeyAMPs,cathelicidinantimicrobialpeptide(CAMP)andhumanbetadefensins(hBDs).However,howexternalperturbationssignaltostimulateAMPproductionhadnotbeenelucidated.Werecentlycharacterizedthatexternalperturbationsinduceendoplasmicreticulum(ER)stressthatincreasestheproductionofaceramidemetabolite,sphingosine1phosphate(S1P),whichinturnstimulatesthekeyantimicrobialpeptide,CAMP,byS1PmediatedtranscriptionfactorNFBwhichthenactivatestranscriptionfactorC/EBP.Wealsofoundthatanotherceramidemetabolite,ceramide1phosphate (C1P),whichisincreasedinresponsetoERstress,increaseshBD2andhBD3productionthroughactivationoftranscriptionfactorsSTAT1andSTAT3,independentofERstressmediatedS1PdependentNFBC/EBPactivation. Ourstudiesdemonstratethatceramideanditsmetabolitesplaycriticalrolesinnotonlytheepidermalpermeabilitybarrier,butalsoincutaneousinnateimmunitythroughstimulationofantimicrobialpeptideproduction.
External Perturbations
(Sub-toxic levels) Cer S1P SPHK1
Nucleus
Sphingosine
Antimicrobial Defense
ER Ceramidase
NF-B activation GlucosylCer
ER stress (Non toxic levels)
C/EBP CAMP
C/EBP activation
CAMP/LL-37
5 3 hBD2/3 5
C1P Cer Kinase
STAT1/3 activation
3
STAT1/3
hBD2/3
SBE
Cer metabolites, S1P- and C1P signaling to stimulate Innate Immunity in Response to External Perturbations
C/EBP
Sphingomyeline