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

Cellular & Molecular Immunology volume 18, pages 2165–2176 (2021)Cite this article

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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.

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Acknowledgements

Yeni Ait Ahmed was a participant in the NIH Graduate Partnerships Program and a graduate student at the Université Paris-Est-Créteil, France, and is affiliated with the Université Paris-Est-Créteil (UPEC) and the NIH Graduate Partnerships Program. 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), and the Ministerio de Economía y Competitividad and European Regional Development Fund RTI2018-101105-B-100 (Juan Hidalgo).

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Authors and Affiliations

  1. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA

    Yeni Ait Ahmed, Yaojie Fu, Robim M. Rodrigues, Yong He, Yukun Guan, Adrien Guillot, Ruixue Ren, Dechun Feng & Bin Gao

  2. Université Paris-Est-Créteil, Créteil, France

    Yeni Ait Ahmed & Fouad Lafdil

  3. Universitat Autònoma de Barcelona, Barcelona, Spain

    Juan Hidalgo

  4. Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA

    Cynthia Ju

  5. INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France

    Fouad Lafdil

  6. Institut Universitaire de France (IUF), Paris, France

    Fouad Lafdil

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Contributions

Y.A.A. designed and performed the surgical procedures and experimental work and wrote the paper. Y.F., R.M.R., Y.H., Y.G., A.G., R.R., and D.F. helped with the PHx surgery, cell isolation, protocol optimization, and other experiments. J.H. and C.J. helped analyze the data and edited the paper. F.L. and B.G. designed and supervised the study and wrote the manuscript.

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Correspondence to Fouad Lafdil or Bin Gao.

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Ait Ahmed, Y., Fu, Y., Rodrigues, R.M. 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 18, 2165–2176 (2021). https://doi.org/10.1038/s41423-021-00731-7

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