Identification of novel oligonucleotides from mitochondrial DNA that spontaneously induce plasmacytoid dendritic cell activation

[摘要] ThisstudytestedthehypothesisthatmtDNAfragmentscarryimmunostimulatorymotifsthatnaturallyinduceimmuneactivationbyPDC.GenomicandmtDNAinducedsimilarIFN‐αproductionaftertransfectionintoPBMCsusingtheliposomaltransfectionreagentDOTAP.ShorteningofmtDNAtoCpGislandsenhancedtheimmunostimulatoryactivity,basedonthepresenceofunmethylatedCpGDNA.FurtherfragmentationintomtODN,whichexhibitedsimilaritiestopublishedCpGODN,resultedinastrongimmunostimulatoryactivityinadditiontoPDCmaturationandmigration.TheadditionofthehumancathelicidinLL‐37toCpGislandsinducedspontaneousPDCIFN‐αproduction.Notably,onephosphodiestermtODNwithadouble‐palindromicstructureinducedPDCIFN‐αproductionintheabsenceofDOTAP.Flowcytometry,life‐cell,andconfocalimagingrevealedattachmentandspontaneousuptakeintoPDC,colocalizing,inpart,withTLR9inearlyendosomalvesicles.ThisprocesswasaccompaniedbyamoderatebutsignificantPDCmaturationinadditiontoBcellandNKcellactivation(P<0.05).Altogether,ourdataindicatethatfragmentedmtDNA,whichmaybereleasedasaconsequenceofapoptotic,necrotic,andnecroptoticcelldeath,canactasaDAMP.Forthefirsttime,ourstudyprovidesamechanismhowlongerandshortermtDNAfragmentscanbetakenupnaturallybythePDCandthus,maycontributetoacuteandchronicimmuneactivation...

[学科分类] 生理学

[关键词] IFN‐αimmune activation;autoimmunity;damage‐associated molecular pattern