Development of tolerogenic dendritic cells and regulatory T cells favors exponential bacterial growth and survival during early respiratory tularemia

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

关键词: NF‐;    κ;    B;    lipopolysaccharide;    neutrophils;    Francisella tularensis ;    IL‐;    10;    TGF‐;    β;   

DOI  :  10.1189/jlb.0411197

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Tularemiaisavector‐bornezoonosiscausedbyFt,aGram‐negative,facultativeintracellularbacterium.Ftexistsintwoclinicallyrelevantforms,theEuropeanbiovarB(holarctica),whichproducesacute,althoughmild,self‐limitinginfections,andthemorevirulentUnitedStatesbiovarA(tularensis),whichisoftenassociatedwithpneumonictularemiaandmoreseveredisease.Inamousemodeloftularemia,respiratoryinfectionwiththevirulence‐attenuatedTypeB(LVS)orhighlyvirulentTypeA(SchuS4)strainengendersperibronchiolarandperivascularinflammation.Paradoxically,despiteanintenseneutrophilicinfiltrateandhighbacterialburden,Th1‐typeproinflammatorycytokines(e.g.,TNF,IL‐1β,IL‐6,andIL‐12)areabsentwithinthefirst∼72hofpulmonaryinfection.IthasbeensuggestedthatthebacteriumhasthecapacitytoactivelysuppressorblockNF‐κBsignaling,thuscausinganinitialdelayinup‐regulationofinflammatorymediators.However,ourpreviouslypublishedfindingsandthosepresentedhereincontradictthisparadigmandinstead,stronglysupportanalternativehypothesis.RatherthanblockingNF‐κB,FtactuallytriggersTLR2‐dependentNF‐κBsignaling,resultinginthedevelopmentandactivationoftDCsandthereleaseofanti‐inflammatorycytokines(e.g.,IL‐10andTGF‐β).Inturn,thesecytokinesstimulatedevelopmentandproliferationofTregsthatmayrestrainTh1‐typeproinflammatorycytokinereleaseearlyduringtularemicinfection.Thehighlyregulatedandoverallanti‐inflammatorymilieuestablishedinthelungispermissiveforunfetteredgrowthandsurvivalofFt.ThecapacityofFttoevokesucharesponserepresentsanimportantimmune‐evasivestrategy...

【 授权许可】

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