20144

201512PAPSBRS

The5thAnnualCongressofPanAsianPacificSkinBarrierResearchSociety

4*(35())201512(PAPSBRS)*: PAPSBRS 14 9(54)74

DATE:November22(W6),2014VENUE:Tainan,Taiwan Organizer:TaiwaneseDermatologicalAssociation

PanAsianPacificSkinBarrierResearchSociety

5th PAPSBRS

9

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.

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.

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.

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,

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)

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.

MaoQiangMan

MaoQiangMangraduatedfromBinzhou

MedicalCollegeinChinain1982and

completedpostdoctoraltrainingatUniversity

ofCaliforniaSanFrancisco.Nowheisa

researchscientistatNorthernCalifornia

InstituteforResearchandEducation.His

researchinterestisregulationofepidermalpermeabilitybarrierfunction,andthe

linkofepidermalpermeabilitybarriertoskinagingandthepathogenesisofskin

disorders.Hehaspublishedover130papersinreputedjournalsandservingasan

editorialboardmemberandinvitedreviewerforanumberofscientificjournals.His

currentHindexis46.

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.

Figure1RegulatoryRolesofEpidermalPermeabilityBarrierinCutaneousFunction.Theepidermalpermeabilitybarrierplayscrucialregulatoryrolesincutaneousfunctions.Disruptionofepidermalpermeabilitybarrierinitiatesawiderangeofcutaneousbiologicalresponses,includingepidermalproliferation,inflammation,andantimicrobialdefense.Decreasedpermeabilitybarrierinducesinflammationandepidermalproliferation,whichcantriggerandexacerbatecertainskindisorders,suchaspruritus,psoriasis,dermatitisaswellasskininfection.Meanwhilebarrierdisruptioninducedepidermalproliferation,lipidproduction/secretionandantimicrobialpeptideexpressionalsoresultinnormalizationofepidermalpermeabilitybarrier,whichinturninhibitcutaneousinflammationandinfection.Approachesthatenhanceepidermalpermeabilitybarriercouldbeanalternativeforpreventingandtreatingcertaindermatoses,includingpruritus,psoriasisanddermatitis.

Figure2SchematicDiagramofEpidermalRoleinthePathogenesisofPsoriasis.Duetoprimarygeneticdefects,theepidermalpermeabilitybarrierisvulnerableinpsoriaticsubjects.Mechanicaltraumas,suchasscratchesorabrasion,damagetheskinbarrier,especiallyduringlowhumidityseasons,suchasthewinter.Whilebarrierfunctioncanbereadilymaintainedinnormalsubjects,inpsoriaticpatients,acompromisedbarriercannotbecompletelyrepairedpossiblyduetothedeficiencyofbarrierrelatedproteinsresultingfromtheunderlyinggeneticdefect.InadditiontohigherskinsurfacepHandlowerstratumcorneumhydrationinwinter,defectivebarrieralonewillelevatethepHofthestratumcorneum,whichinturn,causesfurtherdelaysinbarrierrepair.Asustainedbarrierdefectprovokesexcesskeratinocyteproliferationandinflammation,initiatedinpartbytheproductionofepidermalcytokines,includingIL1,IL1,TNF,IL6,andIL8fromtheepidermis,leadingtoinflammatorycellinfiltrationandepidermalhyperplasia.

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

Society: JapaneseSocietyforInvestigativeDermatology(ChairmanofBoardofDirectors,19982002)JapaneseDermatologicalAssociation(BoardofCouncil,ViceChairmanofBoardofDirector20042006)JapaneseSocietyofMedicalMycology(BoardofCouncil,andDirectors)HonoraryMembershipfromKoreanSocietyforInvestigativeDermatology(2000)EditorialBoard: ArchivesofDermatology(19931997),(EditorialBoardasInternationalAdvisoryCommittee),JournalofDermatologicalScience(1993200,AssociateEditor), EpithelialCellBiology(19921997),JapaneseJournalofMedicalMycology(19871993)

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.

Thisslideshowsthattheepidermiscanbedividedfunctionallyinto3layers.

Thefirstlayerisawaterbarrierformedbylamellarlipidsandasheetofcorneocytes,

rivetedwithcorneodesmosomes.

Thesecondlayerisamolecularbarrierformedbytightjunctionbetween

stratumcorneumandthesecondlayerofgranularcellsfromtheabove.Watercan

freelymovecrossingthetightjunctions.

Thethirdlayerisaprecursorsandsustaininglayerfortheabovetwolayers,

constructedwithakeratinocytesheetboundwithdesmosomesandkeratin

cytoskeletons.

Scratchwoundingon6dayconfluentkeratinocyteculturesactivatesPKCalpha,

SrcandEGFR,causinganalterationofdesmosomesfromhyperadhesivetodynamic

lowaffinityconditions,sothatkeratinocytescouldmigrateoutfromthecolony.

Twostephypothesisofacantholysismechanisminpemphigusvulgaris:

GenerationofDynamic(lowaffinity)Ca2+sensitivedesmosomesandDsg3depletion.

Inculturedkeratinocytes,PVIgGactivatesproteinkinaseCandEGFR,whichalterthe

Ca2+independenthyperadhesivedesmosometoCa2+sensitivedynamic

desmosomesorevenweakenstheadhesivestrength,leadingkeratinocytesto

becomemoresensitivetocellularmechanismsforblisteringprocesses,i.e.,

nonassemblyanddepletionofDsg3indesmosomes.

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.

Thisslideshowshistopathologyanddistributionofcorneodesmosomesin

corneocyteswithincreasedcholesterolsulfate.HistopathologyshowsamoderatedegreeofhyperkeratosiswithcompactSCthatlacksthebasketweavepatternofnormalSC,andwitheitheranormalorthickenedgranularcelllayer.Corneodesmosomesshowahomogenousdottednonperipheraldistribution,becauseofKLKinhibitionbycholesterolsulfate,whichisincreasedduetomutationofcholesterolsulfataseresultingininsufficientenzymaticactivity. Thelossofnormalhoneycombpatternofcorneodesmosomes(CDS)maybeprofoundlyinvolved.Whentheskinisgettinglateralpullingforcesorpressures,theCDShoneycombpatternmaypermittheskintoattenuatesuchforces/pressuresbyallowingthestretchorshrinkageofcorneocyteshapebyslidingofthecentralpartbetweentheupperandlowerSCsinsyncwiththemultilayeredlipidsbetweencorneocytes.ThisallowstheSCtobend/flexwithoutcrackinginnormalepidermalSC.Incontrast,amoregeneralizeddistributionofCDSwouldnotallowforsimilarbending/flexibility,asthewholesurfaceofcorneocyteswouldbefixedtoeachotherviarivetsofCDS;assuch,thecracksintheSCmaybegeneratedtoadjusttothebendingforcesandpressuresinthepatientskinSC.

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.

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.

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.

Figure1Theskinsbarrierfunctionhasthreeelements:thestratumcorneum(airliquidbarrier),tightjunctions(TJs:liquidliquidbarrier),andtheepidermalLangerhanscell(LC)network(immunologicalbarrier). ExternalwatersolubleantigensareconsideredtobeheldoutsideTJbarrierandtakenupbyLCsviatheinsideoutTJpenetrationofLCdendritesuponactivation.

Figure2WefoundthatLangerhanscells(LCs),butnotinflammatorydendriticepidermalcells(IDECs),extendtheirdendritesthroughthetightjunction(TJ)probablytocaptureantigensfromoutsidetheTJbarrierintheerythematouslesionalskinofatopicdermatitis(AD). LangerinwasaccumulatedatthetipoftheTJpenetrateddendrites,whileFcRIwasexpressedbelowTJsbybothLCsandIDECs,possiblytocapturepenetratedantigens. ThebehavioraldifferencesbetweenthetwotypesofdendriticcellsfoundintheskinofADprovideanimportantframeworktodissectthepathophysiologyofAD.

JiaYouFang,Ph.D

Address:261WenHwa1stRoad,Kweishan,Taoyuan333,

Taiwan

Phone:88632118999ext5715

Fax:88632118236

Email: fajy@mail.cgu.edu.tw

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.

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

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

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.

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

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.

YoshikazuUchidaPosition: ResearchScientist(Dermatology) Address:DermatologyService(190),VeteransAdministrationMedicalCenter,1700OwensStreet,Room326,SanFrancisco,CA94158Tel:(415)5750524,Fax: (415)7502106Email:uchiday@derm.ucsf.eduEDUCATION1982 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

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

3.UchidaY.Theroleoffattyacidelongationinepidermalstructureandfunction.Dermato

Endocrinol3:659,2011

4.UchidaY.Ceramidesignalingintheepidermis.BiolBiochemActa1841:45362,2014

5.EliasP.M.,GruberR.,CrumrineD.,MenonG.,WilliamsM.,WakefieldJ.S.,HolleranW.M.,

andUchidaY.FormationandFunctionsoftheCorneocyteLipidEnvelope(CLE)Biochim

BiophysActa.1841:31418,2014.

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