18may2017|VOL545|NaTURE|305aRTicLEdoi:10.1038/nature22075EndothelialTLR4andthemicrobiomedrivecerebralcavernousmalformationsalanT.Tang1,JaesungP.choi2,JonathanJ.Kotzin3,4,yiqingyang1,courtneyc.Hong1,NicholasHobson5,RomualdGirard5,Husseina.Zeineddine5,RhondaLightle5,Thomasmoore5,yingcao5,RobertShenkar5,meichen1,Patriciamericko1,Jishengyang1,LiLi1,ceylanTanes6,DmytroKobuley4,7,UrmoVõsa8,KevinJ.Whitehead9,Deany.Li9,LudeFranke8,BlaineHart10,markusSchwaninger11,JorgeHenao-mejia3,4,12,Lesliemorrison10,HelenKim13,issama.awad5,XiangjianZheng2,14,15&markL.Kahn1CCMsarerelativelycommonvascularmalformationsthatarisepre-dominantlyinthecentralnervoussystem,causinghaemorrhagicstrokeandseizure1.CCMsarisefromlossoffunctionmutationsinthreegenes,KRIT1,CCM2andPDCD10,thatencodecomponentsofaheterotrimeric,intracellularadaptorproteincomplex(the‘CCMcomplex’)2,3.TheclinicalcourseoffamilialCCMdiseaseishighlyvariable,evenamongindividualswhoshareidenticalgermlinemutations4–6,suggestingtheexistenceofpowerfulgeneticand/orenvironmentaldiseasemodifiers.PresenttreatmentforCCMsconsistssolelyofpalliativetherapiesorneurosurgicalresection.PreviousstudiesofvertebrategeneticmodelsandhumanCCMlesionshavedemonstratedthatlossoftheCCMcomplexresultsinvascularlesionformationowingtoincreasedMEKK3–KLF2/4signal-linginbrainendothelialcells7–10,andthattheCCMcomplexsuppressesMEKK3–KLF2/4signallingthroughadirectinteractionbetweenCCM2andMEKK3(refs11,12).AsthereisalackofeffectivedrugsthattargettheMEKK3–KLF2/4pathway,thesemolecularinsightshavenotbeenimmediatelytranslational.However,theyraiseakeymechanisticquestion:iftheroleoftheCCMcomplexistonegativelyregulateMEKK3–KLF2/4signalling,whatactivatesthispathwayinbrainendothelialcells?IdentificationofupstreamactivatorsofthispathwayisneededtounderstandthepathogenesisofCCMdiseaseandrevealviabletherapeuticstrategies.CCMformationisdrivenbyGNBandLPSToinvestigateCCMformationinmice,wegeneratedanimalsinwhichendothelial-specificdeletionofKrit1orCcm2wasinducedonedayafterbirth...
