NFI‐A disrupts myeloid cell differentiation and maturation in septic mice

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

关键词: sepsis;    inflammation;    MDSC;    immune suppression;    microRNA;   

DOI  :  10.1189/jlb.4A0415-171RR

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Mountingevidencesupportsthatsepsis‐associatedimmunosuppressionincreasesmortality.Aspotentialcontributorstopoorsepsisoutcomes,myeloid‐derivedsuppressorcells,whichareGr1+CD11b+innate‐immunecellprogenitorsunabletodifferentiateandpossesssuppressiveactivities,expanddramaticallyinsepticmicebyaprocessrequiringincreasedmicroRNA‐21andmicroRNA‐181bexpression.TheinhibitionofthesemicroRNAsinvivoinsepticmicerestoresGr1+CD11b+celldifferentiationandmaturationandimprovessurvival.Here,weshowthatduringsepsis‐inducedgenerationofmyeloid‐derivedsuppressorcells,transcriptionfactornuclearfactor1Atyperepressescyclin‐dependentkinaseinhibitorp21toarrestdifferentiationofGr1+CD11b+cells.Ourfindingsincludethefollowing:1)Gr1+CD11b+myeloidcellsfromlatesepticmicegeneticallylackingnuclearfactor1AtypecannotsuppressCD4+Tcellproliferationandactivation;2)thereconstitutionofnuclearfactor1AtypeinmicroRNA‐21andmicroRNA‐181b‐depletedGr1+CD11b+myeloid‐derivedsuppressorcellsinhibitscyclin‐dependentkinaseinhibitorp21andrestorestheimmune‐suppressorphenotype;3)exvivonuclearfactor1AtypeknockdowninGr1+CD11b+myeloid‐derivedsuppressorcellsfromlatesepticmicerestorescyclin‐dependentkinaseinhibitorp21expressionandpromotesmonocyteanddendriticcelldifferentiation;and4)ectopicnuclearfactor1AtypeexpressioninnormalGr1+CD11b+cellsgeneratesanimmunosuppressivephenotype.Wesuggestthattherapeuticallytargetingnuclearfactor1Atypeduringlatesepsismightimprovesurvival...

【 授权许可】

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