IL‐8‐mediated angiogenic responses of endothelial cells to lipid antigen activation of iNKT cells depend on EGFR transactivation

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: α;    ‐;    galactosylceramide;    inflammation;    atherosclerosis;    neovascularization;    endothelial cell;    signal transduction;    inhibition;   

DOI  :  10.1189/jlb.0211097

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

iNKTcellsareauniqueTcellsubset,whichisCD1d‐restrictedandspecificforglycolipidantigens.Inadvancedatheroscleroticplaques,focalcollectionsofinflammatorycellscorrelatewithareasofintraplaqueneovascularization.WereportedrecentlythatiNKTcellsmightfacilitateintraplaqueneovascularizationbyenhancingECmigrationandsproutinginanIL‐8‐dependentmanner.Thisstudyinvestigatedtheparticipatingeffectormechanisms.InECs,CM,derivedfromantigen‐stimulatedhumaniNKTcells(CM+),inducedup‐regulationofIL‐8RCXCR2andthephosphorylationofEGFRandofmultipleintracellularsignalingeffectors,includingFAK,Src,Erk,Jnk,p38‐MAPK,andSTAT1and‐3.Wefoundthatacascadeofevents,whichwereIL‐8‐dependentandinvolvedEGFRactivation,wasresponsibleforsignalingthroughFAKandSrckinasesandnecessaryforacquisitionofangiogenicmorphology,migrationinatwo‐dimensionalwoundassay,andsproutoutgrowthinathree‐dimensionalmodelofangiogenesisinvitro.ThedatasupportthatIL‐8‐dependentactivationofangiogenicbehaviorinECs,inresponsetoactivatediNKT,involvesCXCR2,transactivationofEGFR,andsubsequentFAK/Srcsignaling.WefoundtoothatactivatediNKTincreasedVEGFR2expressioninECs.FunctionalstudiesconfirmedthatEGFisthemotogenic‐enhancingfactorinCM+andisnecessary,togetherwithanexogenoussourceofVEGF,foriNKT‐promotedsproutformation.EGFRinhibitionmayrepresentanoveltherapeuticmodalityaimedatplaquestabilizationthroughcontrolofneovascularizationwithindevelopingatheroscleroticplaques...

【 授权许可】

CC BY