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Ait Ahmed Y, Fu Y, Rodrigues RM, et al. Kupffer cell restoration after partial hepatectomy is mainly driven by local cell proliferation in IL-6-dependent autocrine and paracrine manners. Cell Mol Immunol. 2021;18(9):2165-2176doi: 10.1038/s41423-021-00731-7.
Ait Ahmed, Y., Fu, Y., Rodrigues, R. M., He, Y., Guan, Y., Guillot, A., Ren, R., Feng, D., Hidalgo, J., Ju, C., Lafdil, F., & Gao, B. (2021). Kupffer cell restoration after partial hepatectomy is mainly driven by local cell proliferation in IL-6-dependent autocrine and paracrine manners. Cellular & molecular immunology, 18(9), 2165-2176. https://doi.org/10.1038/s41423-021-00731-7
Ait Ahmed, Yeni, et al. "Kupffer cell restoration after partial hepatectomy is mainly driven by local cell proliferation in IL-6-dependent autocrine and paracrine manners." Cellular & molecular immunology vol. 18,9 (2021): 2165-2176. doi: https://doi.org/10.1038/s41423-021-00731-7
Ait Ahmed Y, Fu Y, Rodrigues RM, He Y, Guan Y, Guillot A, Ren R, Feng D, Hidalgo J, Ju C, Lafdil F, Gao B. Kupffer cell restoration after partial hepatectomy is mainly driven by local cell proliferation in IL-6-dependent autocrine and paracrine manners. Cell Mol Immunol. 2021 Sep;18(9):2165-2176. doi: 10.1038/s41423-021-00731-7. Epub 2021 Jul 19. PMID: 34282300; PMCID: PMC8429713.
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Cell Mol Immunol. 2021 Sep;18(9):2165-2176. doi: 10.1038/s41423-021-00731-7. Epub 2021 Jul 19.

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

Cellular & molecular immunology

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

Affiliations

  1. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
  2. Université Paris-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. Université Paris-Est-Créteil, Créteil, France. [email protected].
  6. INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France. [email protected].
  7. Institut Universitaire de France (IUF), Paris, France. [email protected].
  8. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA. [email protected].

PMID: 34282300 PMCID: PMC8429713 DOI: 10.1038/s41423-021-00731-7

Abstract

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.

© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Keywords: IL-6; Kupffer cells; Liver regeneration; Myeloid cells; Sirtuin 1

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