mucosal barrier.docx
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mucosal barrier.docx
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mucosalbarrier
Panethcellantimicrobialpeptidesandthebiologyofthemucosalbarrier
AndreJ. Ouellette
AmericanJournalofPhysiology-GastrointestinalandLiverPhysiologyPublished1August1999Vol. 277no. 2,G257-G261DOI:
ABSTRACT
Thehypothesisthatepithelialcellsreleasepreformedantibioticpeptidesascomponentsofmucosalinnateimmunityhasgainedexperimentalsupportinrecentyears.Inthemammaliansmallintestine,Panethcellssecretegranulesthatarerichinα-defensinsandadditionalantimicrobialpeptidesintothelumenofthecrypt.Theα-defensinsarehomologuesofpeptidesthatfunctionasmediatorsofnonoxidativemicrobialcellkillinginphagocyticleukocytes,andtheyarepotentmicrobicidalagentsininvitroassays.Becausecertainmouseα-defensinsstimulateculturedepithelialcellstosecretechlorideion,thosepeptidesappeartobecapableofinteractingdirectlywiththeapicalmembranesofneighboringcellsandperhapsinfluencingcryptphysiology.IninstancesofcryptdisruptionorinducedPanethcelldeficiency,cryptintermediatecellsappeartocompensatebyaccumulatingandsecretingPanethcellantimicrobialpeptides.ChallengesforthefuturewillbetounderstandthemechanismsofthisepithelialplasticityandtoshowthatPanethcellscontributedirectlytoinnateimmunityinthecryptmicroenvironment.
THEEPITHELIALMONOLAYER thatlinesthemammaliansmallintestineisboththerouteofnutrientabsorptionandanactivebarrierbetweentheexternalenvironmentandthecirculation.Atfirstappearances,adaptationsofthesmallboweltoimprovenutrientuptakebyamplificationofabsorptivesurfaceareawouldseemtoincreasetheriskofmucosalcolonizationbypotentialpathogens.Nevertheless,thebacterialloadofthesmallbowelremainsverylowrelativetothatofthecolon.
Manyfactorscontributetothelowbacterialnumbersofthesmallintestine.Examplesincludethenormalphysiologicalactivitiesofthegutsuchasmotility,secretionofdigestiveandpancreatobiliaryjuices,mucoussecretionsofgobletcells,andhumoralandcytotoxicimmuneresponsesofBandTlymphocytestospecificantigens.Inaddition,however,epithelialcellsareknowntoactivelyreleasegene-encoded,antibioticpeptidesthatcontributetoabiochemicalbarrieragainstmicrobialcolonization.Inadditiontothestudiesofsmallintestinalantimicrobialpeptidestobereviewedbrieflyhere,severalinvestigatorshaveshownthatthemucosaoftheairway,skin,gingiva,tongue,cornea,reproductivetract,urogenitaltract,andcolonalsoparticipateininnateimmunity(6).
ANTIMICROBIALPEPTIDES
Theproductionofantimicrobialproteinsandpeptidesiswidelydistributedphylogenetically.Originallydescribedasresponsesofcirculatinghemocytestocuticleinjuryininsectlarvae,antimicrobialpeptidesarenowrecognizedaseffectorsofabiochemicalbarrieragainstpotentialpathogensinplants,insects,amphibia,teleosts,andmammals(15).Selectivepressureforthesynthesisandreleaseofantimicrobialpeptidesinresponsetoinfection,ortheconstantthreatofinfection,appearstohavebeenwidespread,sincepeptideswithpotentinvitroantimicrobialactivitieshavebeenisolatedfromallphylaexamined,includingplants,invertebrates,andspecieslackingclonalimmunemechanisms(14).Thesepreformedpeptideantibioticsarehighlyvariableinprimarystructure,andtheymaybeinducible,synthesizedcontinuallyandaccumulateincytoplasmicgranulesforregulatedsecretion,ortheymaybereleasedonaconstitutivebasis.
Gastrointestinalexpressionofantimicrobialpeptidesalsoisevolutionarilyconserved.Inthegastrointestinaltractofthefrog,forexample,magainins,theprimaryantimicrobialpeptidesoffrogskin,arefoundinstomachglands,andtheyalsoarepresentinglandsatthebaseofepithelialfoldsinthefrogintestine(32).Ininvertebrates,midgutproductionofinsectdefensinsbecomesactivatedinthemosquitoand Stomoxyscalcitrans afterconsumptionofabloodmeal(5, 21),andthemidgutof Manducasexta larvaecontainsantimicrobialpeptidesingranules(21).Thesefindingssuggestthattheproductionandsecretionofantimicrobialpeptidesbymammalianintestinalepitheliaisaconservedinnateimmunemechanismratherthanarecentevolutionarydevelopment.
Mostantimicrobialpeptidesexpressedbymammalianepithelialcellsaremembersofpeptidefamiliesthatmediatenonoxidativemicrobialcellkillingbyphagocytes(15).Inpolymorphonuclearleukocytes,thepeptidesarestoredintheazurophilicgranules,andtheymediatekillingofingestedmicroorganismsfollowingphagolysosomalfusion.Epithelialpeptides,ontheotherhand,appeartofunctionintheextracellularcompartmentattheinterfacewiththeexternalenvironment(26).Thecolonic,airway,andreproductiveepithelialcellsappeartoreleaseantimicrobialpeptidescontinuallyorconstitutively.Inthesmallintestine,microbicidalpeptidesaccumulateinsecretorygranulesofPanethcellsforapicalreleasebyregulatedexocytosis.Becauseepithelialantimicrobialpeptidesarehomologoustopeptidesintheazurophilicgranulesofneutrophils,e.g.,defensins,andbecausethosepeptidesaremicrobicidalininvitroassays,theyareimplicatedinimmunityatthemucosalsurface.
ANTIMICROBIALPEPTIDESINPANETHCELLS
PanethcellsarelocatedatthebaseofthecryptsofLieberkühninthesmallintestineofmanymammalianspecies.Theyarerecognizedbytheunusuallylargeapicalsecretorygranulesthattheyreleaseintothecryptlumen.MostsmallintestinalcryptsarepopulatedbyPanethcells,and,inmice,amplificationofα-defensincDNAsequencesinisolatedcryptsbyRT-PCRhasshownthateverycryptcontainsPanethcellsorPanethcelltranscripts(3).Asidefromtheirunusualmorphology,Panethcellshavecertaincharacteristicfeatures.Forexample,althoughtheyoriginatefromthesamecryptstemcellsthatgenerateallintestinalepithelialcelllineages,theydifferentiateduringdownwardmigrationfromtheproliferativezone
(2).Incontrast,theotherepithelialcellpopulationsdifferentiateterminallyastheyascendthecryptsandmigratealongthevillitowardtheireventualexfoliation.Also,Panethcellshavea20dayaveragelifespan,unlikevillousenterocytesthatapoptoseandexfoliateintothelumen2–5daysafteremergencefromthestemcellzone.Histologically,normalPanethcellsdevelopundergerm-freeconditionsandfrommurineorhumanfetalintestinalxenograftsinnudemice(20),demonstratingthatPanethcellontogenydoesnotrequireluminalbacteriaordietaryconstituents.
InsightsintoPanethcellfunctionhavebeenprovidedbyanalysesoftheirgeneproducts.Forexample,secretionoflysozymeandhomologuesofphagocyticantimicrobialpeptidesimplicatesPanethcellsinenterichostdefense.Specifically,Panethcelllysozyme,secretoryphospholipaseA2(sPLA2),andα-defensinshavewell-establishedantimicrobialactivitieswhenassayedinvitro(16).Inmice,thesegeneproductsappearduringpostnatalcryptontogeny,coincidentwithPanethcelldifferentiation,andtheyareusefulmarkersofthelineage.ThesecretionofthisarrayofpeptideantibioticsbythePanethcell,thedefensinsinparticular,isconsistentwithaninnateimmunerole.
DEFENSINS
Twoknowndefensinpeptidesubfamilieshavebeenwelldescribed,theα-andβ-defensins.Bothsubfamiliescomprisecationic,3-to4-kDapeptidesthatcontainsixcysteineresiduesinthreedisulfidebonds.AlthoughtheirtridisulfidearraysdifferintheirCys-Cyspairings,α-andβ-defensinshaveremarkablysimilarfoldedconformations(29).Themammalianα-defensinsaremajorconstituentsoftheprimarygranulesinphagocyticleukocytesofmyeloidorigin,andtheywereoneofthefirstantimicrobialpeptidefamiliestoberecognized(6).Theβ-defensinsoccurinmoretissuesthantheα-defensins,buttheyhavenotbeendetectedinPanethcellstomyknowledge.Theyareexpressedinbovinebonemarrowandinthemucosaofthecolon,airway,tongue,kidney,skin,andgingivainhumansandinotherspecies.Inhibitionofhumanβ-defensin-1antibacterialactivitybythehighionicstrengthofairwaysurfacefluidofcysticfibrosispatientshasbeenimplicatedinmicrobialpathogenesisassociatedwiththedisease(4);nevertheless,themechanismsinvolvedremainunresolved.Severalyearssubsequenttotheirdiscoveryinneutrophils,α-defensinswereidentifiedinmouseandhumanPanethcells(16).
ENTERIC-DEFENSINS
α-DefensinsareabundantconstituentsofmouseandhumanPanethcellgranules.HumanPanethcellscodefortwoα-defensinpeptides,HD-5andHD-6,andmiceexpressnumerousPanethcellα-defensinisoforms,termed“cryptdins”forcryptdefensin.Sixcryptdinshavebeenpurifiedtohomogeneity(16).Immunohistochemicalstudiesofsmallintestinalsectionshaveshownthatantibodiestomousecryptdin-1andrecombinantHD-5reactexclusivelywithPanethcellsoftherespectivespecies(17, 25).ImmunogolddetectionexperimentsshowthattheantigenisdistributeduniformlyinPanethcellgranules(17).Inmice,individualisoformsdifferinrelativeabundanceinthatwholeorganrecoveriesofcryptdins-1,-2,-5,and-6areequivalentbutlevelsofcryptdins-3and-4aremuchlower.Theprimarystructuresofcryptdins-4and-5divergemarkedlyfromeachotherandfromthemajorityofcryptdinsthatarevariablysubstitutedvariantsofcryptdin-1(16).Cryptdins-2and-3,forexample,differinsequenceonlyatposition10(Thrvs.Lys,respectively).Cryptdin-4isthemostcathodalentericdefensinandthefirstα-defensintocontainachain-lengthvariationbetweenthefourthandfifthcysteineresidues.Furthermore,cryptdin-4geneisuniquebecauseitisexp
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