Kupffer cell restoration after partial hepatectomy is mainly driven by local cell proliferation in IL-6-dependent autocrine and paracrine manners  

作　　者：Yeni Ait Ahmed Yaojie Fu Robim M.Rodrigues Yong He Yukun Guan Adrien Guillot Ruixue Ren Dechun Feng Juan Hidalgo Cynthia Ju Fouad Lafdil Bin Gao 

机构地区：[1]Laboratory of Liver Diseases,National Institute on Alcohol Abuse and Alcoholism,National Institutes of Health,Bethesda,MD,USA [2]UniversitéParis-Est-Créteil,Créteil,France [3]Universitat Autònoma de Barcelona,Barcelona,Spain [4]Department of Anesthesiology,McGovern Medical School,University of Texas Health Science Center at Houston,Houston,TX,USA [5]INSERM U955,Institut Mondor de Recherche Biomédicale,Créteil,France [6]Institut Universitaire de France(IUF),Paris,France

出　　处：《Cellular & Molecular Immunology》2021年第9期2165-2176,共12页中国免疫学杂志（英文版）

基　　金：This work was supported by the intramural program of the NIAAA(Bin Gao);the NIH grant R01DK121330,R01DK 122708,R01DK122796(Cynthia Ju);the Institut Universitaire de France(Fouad Lafdil);the Ministerio de Economía y Competitividad and European Regional Development Fund RTI2018-101105-B-100(Juan Hidalgo).

摘　　要：Kupffer cells(KCs),which are liver-resident macrophages,originate from the fetal yolk sac and represent one of the largest macrophage populations in the body.However,the current data on the origin of the cells that restore macrophages during liver injury and regeneration remain controversial.Here,we address the question of whether liver macrophage restoration results from circulating monocyte infiltration or local KC proliferation in regenerating livers after partial hepatectomy(PHx)and uncover the underlying mechanisms.By using several strains of genetically modified mice and performing immunohistochemical analyses,we demonstrated that local KC proliferation mainly contributed to the restoration of liver macrophages after PHx.Peak KC proliferation was impaired in Il6-knockout(KO)mice and restored after the administration of IL-6 protein,whereas KC proliferation was not affected in Il4-KO or Csf2-KO mice.The source of IL-6 was identified using hepatocyte-and myeloid-specific Il6-KO mice and the results revealed that both hepatocytes and myeloid cells contribute to IL-6 production after PHx.Moreover,peak KC proliferation was also impaired in myeloid-specific Il6 receptor-KO mice after PHx,suggesting that IL-6 signaling directly promotes KC proliferation.Studies using several inhibitors to block the IL-6 signaling pathway revealed that sirtuin 1(SIRT1)contributed to IL-6-mediated KC proliferation in vitro.Genetic deletion of the Sirt1 gene in myeloid cells,including KCs,impaired KC proliferation after PHx.In conclusion,our data suggest that KC repopulation after PHx is mainly driven by local KC proliferation,which is dependent on IL-6 and SIRT1 activation in KCs.

关 键 词：IL-6 Sirtuin 1 Liver regeneration Kupffer cells Myeloid cells 

分 类 号：R392[医药卫生—免疫学]