ADAM9 disintegrin domain activates human neutrophils through an autocrine circuit involving integrins and CXCR2

[摘要] ADAM9isamemberoftheADAMfamilywhoseexpressionpositivelycorrelateswithtumorprogression.Besidesthemetalloproteaseactivity,ADAM9Dinteractswithdifferentintegrins,modulatingcell‐adhesionevents.Previousstudiespointedtoanimportantroleforneutrophilsintumordevelopment,astheinhibitionofneutrophilmigrationordepletionofthisimmunecellimpairstumorgrowth.However,ourunderstandingofthemolecularmechanismsinvolvedinthisprocess,aswellasthemainkeyplayersactingonneutrophils,isverylimited.Here,weinvestigatedthepossiblemodulatoryeffectsofADAM9Donhumanneutrophilfunctions.OurresultsshowthatADAM9Dpromotesneutrophilactivationandchemotaxisinaprocessthatdependsontheengagementofαvβ3andα9β1integrinsandontheactivationofPI3K/AktandMAPKsignalingpathway.ADAM9DimpairsmigrationofneutrophilstowardfMLP,LTB4,andIL‐8asclassicchemoattractants.ThiseffectisblockedbyPTX,aG(i)PCRinhibitor.Furthermore,CXCR2antagonistsRPTXandSB225002alsoimpairedneutrophilchemotaxisinresponsetoADAM9D,suggestingahierarchicalcross‐talkofintegrinswithCXCR2.OurresultsindicatethatADAM9Dactivatesneutrophilfunctionsandmaybeimplicatedintheinflammatoryeventsassociatedwithcancerandotherdisorders...

[学科分类] 生理学

[关键词] signal transduction;granulocyte;chemotaxis;apoptosis;IL‐8