Carl-PhilippHackstein,LisaMareikeAssmus,MeikeWelz,SabineKlein,TimoSchwandt,JoachimSchultze,IrmgardF?rster,FabianGondorf,MarcBeyer,DanielaKroy,ChristianKurts,JonelTrebicka,WolfgangKastenmüller,PercyAKnolle,ZeinabAbdullah
本刊负责人：医院北京大学肝病研究所
审校：韩国宏空**医院消化介入科
翻译：汤世豪李凯空**医院消化介入科
摘要
目的：肝硬化患者更易发生致死性细菌感染，进而导致实质性的病症。
方法：通过胆管结扎或四氯化碳（carbontetrachloride，CCl4）诱导建立肝纤维化小鼠模型，研究固有免疫系统抗感染失败的机制。
结果：在肝纤维化小鼠模型中，肠道菌群移位可诱导肝内I型干扰素（interferon，IFN）表达上调，进而促使肝髓样细胞在感染李斯特菌后激活胞内模式识别受体产生高浓度的IFN。IFN受体信号通路介导肝髓样细胞产生白介素10（interleukin-10，IL-10），后者可破坏抗菌免疫功能，进而导致感染失控及感染相关性死亡。而肝硬化患者在细菌感染后，同样观察到了上述现象。因此，对于IFN诱发和IL-10介导的免疫功能障碍，肝髓样细胞既是产生原因，也是作用靶标。用抗体阻断IFN或IL-10受体信号通路可重建抗菌免疫功能，并降低肝纤维化模型小鼠的感染相关死亡风险。
结论：在重症肝纤维化和肝硬化患者中，IFN和IL-10的表达增加会破坏肝髓样细胞的抗菌免疫功能，导致细菌感染失控。靶向干预宿主免疫因子IL-10和IFN的表达有利于重建抗菌免疫功能，或可作为肝硬化患者预防细菌感染的治疗策略。
Gutmicrobialtranslocationcorruptsmyeloidcellfunctiontocontrolbacterialinfectionduringlivercirrhosis
Carl-PhilippHackstein,LisaMareikeAssmus,MeikeWelz,SabineKlein,TimoSchwandt,JoachimSchultze,IrmgardF?rster,FabianGondorf,MarcBeyer,DanielaKroy,ChristianKurts,JonelTrebicka,WolfgangKastenmüller,PercyAKnolle,ZeinabAbdullah
ABSTRACT
ObjectivePatientswithlivercirrhosissufferfromincreasedsusceptibilitytolife-threateningbacterialinfectionsthatcausesubstantialmorbidity.
MethodsExperimentalliverfibrosisinmiceinducedbybileductligationorCCl4applicationwasusedtocharacterisethemechanismsdeterminingfailureofinnateimmunitytocontrolbacterialinfections.
ResultsInmurineliverfibrosis,translocationofgutmicrobiotainducedtonictypeIinterferon(IFN)expressionintheliver.SuchtonicIFNexpressionconditionedlivermyeloidcellstoproducehighconcentrationsofIFNuponintracellularinfectionwithListeriathatactivatecytosolicpatternrecognitionreceptors.SuchIFN-receptorsignallingcausedmyeloidcellinterleukin(IL)-10productionthatcorruptedantibacterialimmunity,leadingtolossofinfectioncontrolandtoinfection-associatedmortality.Inpatientswithlivercirrhosis,wealsofoundaprominentliverIFNsignatureandmyeloidcellsshowedincreasedIL-10productionafterbacterialinfection.Thus,myeloidcellsarebothsourceandtargetofIFN-inducedandIL-10-mediatedimmunedysfunction.Antibody-mediatedblockadeofIFN-receptororIL-10-receptorsignallingreconstitutedantibacterialimmunityandpreventedinfection-associatedmortalityinmicewithliverfibrosis.
ConclusionsInsevereliverfibrosisandcirrhosis,failuretocontrolbacterialinfectioniscausedbyaugmentedIFNandIL-10expressionthatincapacitatesantibacterialimmunityofmyeloidcells.TargetedinterferencewiththeimmuneregulatoryhostfactorsIL-10andIFNreconstitutesantibacterialimmunityandmaybeusedastherapeuticstrategytocontrolbacterialinfectionsinpatientswithlivercirrhosis.
GutMar,66（3）-;DOI:10./gutjnl--