Anti-inflammatoryeffectofIL-10mediatedbymetabolicreprogrammingofmacrophagesW.K.EddieIp1,NamikoHoshi1,*,DrorS.Shouval2,†,ScottSnapper2,andRuslanMedzhitov1,‡1DepartmentofImmunobiologyandHowardHughesMedicalInstitute,YaleUniversitySchoolofMedicine,NewHaven,CT06510,USA.2BostonChildren’sHospital,HarvardMedicalSchool,Boston,MA02115,USA.AbstractInterleukin10(IL-10)isananti-inflammatorycytokinethatplaysacriticalroleinthecontrolofimmuneresponses.However,itsmechanismsofactionremainpoorlyunderstood.Here,weshowthatIL-10opposestheswitchtothemetabolicprograminducedbyinflammatorystimuliinmacrophages.Specifically,weshowthatIL-10inhibitslipopolysaccharide-inducedglucoseuptakeandglycolysisandpromotesoxidativephosphorylation.Furthermore,IL-10suppressesmammaliantargetofrapamycin(mTOR)activitythroughtheinductionofanmTORinhibitor,DDIT4.Consequently,IL-10promotesmitophagythateliminatesdysfunctionalmitochondriacharacterizedbylowmembranepotentialandahighlevelofreactiveoxygenspecies.IntheabsenceofIL-10signaling,macrophagesaccumulatedamagedmitochondriainamousemodelofcolitisandinflammatoryboweldiseasepatients,andthisresultsindysregulatedactivationoftheNLRP3inflammasomeandproductionofIL-1β.Interleukin-10(IL-10)isakeyanti-inflammatorycytokineproducedbyactivatedimmunecells(1).AlthoughmosthematopoieticcellssenseIL-10viaexpressionofIL-10receptor(IL-10R),recentstudieshaveshownthatmacrophagesarethemaintargetcellsoftheinhibitoryIL-10effects(2,3).PolymorphismsintheIl10locusconferriskforinflammatoryboweldisease(IBD),includingulcerativecolitisandCrohn’sdisease(4,5),andmiceandhumansdeficientineitherIL-10orIL-10Rexhibitsevereintestinalinflammation(2,3,6,7),indicatingthattheIL-10-IL10RaxisplaysanessentialroleinregulationofintestinaltissuehomeostasisandpreventionofIBD.Littleisknownaboutthemolecularbasisoftheanti-inflammatoryactivitiesofIL-10(8).UnderstandingtheroleofIL-10intheregulationofmetabolicprocessesisessentialbothfordecipheringhowIL-10actstocontrolinflammatoryexclusivelicenseeAmericanAssociatio...
