The Src kinase Fyn is protective in acute chemical‐induced colitis and promotes recovery from disease

[摘要] Despiteprogressinunderstandingentericinflammation,currenttherapies,althougheffectiveinmanypatientswithinflammatoryboweldisease(IBD),havesignificantside‐effects,and,inmanypatients,itisrefractorytotreatment.TheSrckinaseFynmediatedIFN‐γ‐inducedincreasedpermeabilityinmodelepithelia,andsowehypothesizedthatinhibitionofFynkinasewouldbeanti‐colitic.Mice[B6.129SF2/Jwild‐type(WT),FynKO,orchimeras]received2.5%dextransodiumsulfate(DSS)ornormalwaterfor10dandwerenecropsiedimmediatelyor3dlater.GutpermeabilitywasassessedbyFITC‐dextranflux,colitisbymacroscopicandhistologicparameters,andimmunecellstatusbycytokineproductionandCD4+TcellFoxp3expression.FynKOmiceconsistentlydisplayedsignificantlyworseDSS‐induceddiseasethanWT,correlatingwithdecreasedIL‐10andincreasedIL‐17insplenocytesandthegut;FynKOmicefailedtothriveafterremovaloftheDSSwater.AnalysisofchimericmiceindicatedthattheincreasedsensitivitytoDSSwasduetothelackofFynkinaseinhematopoietic,butnotstromal,cells,inaccordancewithFyn+TcellincreasesinWTmiceexposedtoDSSandFynKOmicehavingareducednumberofCD4+Foxp3+cellsinbaselineorcoliticconditionsandareducedcapacitytoinduceFoxp3expressioninvitro.OtherexperimentssuggestthatthecolonicmicrobiotainFynKOmiceisnotpreferentiallycolitogenic.Contrarytoourexpectation,theabsenceofFynkinaseresultedingreaterDSS‐induceddisease,andanalysisofchimericmiceindicatedthatleukocyteFynkinaseisbeneficialinlimitingcolitis...

[学科分类] 生理学

[关键词] inflammatory bowel disease;Foxp3;regulatory T cell;dextran sodium sulfate