Kupffer cell restoration after partial hepatectomy is mainly driven by local cell proliferation in IL-6-dependent autocrine and paracrine manners.
IL-6
Kupffer cells
Liver regeneration
Myeloid cells
Sirtuin 1
Journal
Cellular & molecular immunology
ISSN: 2042-0226
Titre abrégé: Cell Mol Immunol
Pays: China
ID NLM: 101242872
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
12
01
2021
accepted:
22
06
2021
pubmed:
21
7
2021
medline:
1
4
2022
entrez:
20
7
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34282300
doi: 10.1038/s41423-021-00731-7
pii: 10.1038/s41423-021-00731-7
pmc: PMC8429713
doi:
Substances chimiques
Interleukin-6
0
interleukin-6, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2165-2176Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK121330
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK122708
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK122796
Pays : United States
Informations de copyright
© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
Références
Dong Z, Wei H, Sun R, Tian Z. The roles of innate immune cells in liver injury and regeneration. Cell Mol Immunol. 2007;4:241–52.
pubmed: 17764614
Markose D, Kirkland P, Ramachandran P, Henderson NC. Immune cell regulation of liver regeneration and repair. J Immunol Regen Med. 2018;2:1–10.
Gao B, Jeong W-I, Tian Z. Liver: an organ with predominant innate immunity. Hepatology. 2008;47:729–36.
pubmed: 18167066
doi: 10.1002/hep.22034
Heymann F, Tacke F. Immunology in the liver—from homeostasis to disease. Nat Rev Gastroenterol Hepatol. 2016;13:88–110.
pubmed: 26758786
doi: 10.1038/nrgastro.2015.200
Merlin S, Bhargava KK, Ranaldo G, Zanolini D, Palestro CJ, Santambrogio L, et al. Kupffer cell transplantation in mice for elucidating monocyte/macrophage biology and for potential in cell or gene therapy. Am J Pathol. 2016;186:539–51.
pubmed: 26773351
pmcid: 4816709
doi: 10.1016/j.ajpath.2015.11.002
Nguyen-Lefebvre AT, Horuzsko A. Kupffer cell metabolism and function. J Enzymol Metab. 2015;1:101.
pubmed: 26937490
pmcid: 4771376
Wen Y, Lambrecht J, Ju C, Tacke F. Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities. Cell Mol Immunol. 2021;18:45–56.
pubmed: 33041338
doi: 10.1038/s41423-020-00558-8
Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol. 2017;17:306–21.
pubmed: 28317925
doi: 10.1038/nri.2017.11
Cai J, Zhang X-J, Li H. The role of innate immune cells in nonalcoholic steatohepatitis. Hepatology. 2019;70:1026–37.
pubmed: 30653691
doi: 10.1002/hep.30506
Wang H, Mehal W, Nagy LE, Rotman Y. Immunological mechanisms and therapeutic targets of fatty liver diseases. Cell Mol Immunol. 2021;18:73–91.
pubmed: 33268887
doi: 10.1038/s41423-020-00579-3
Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol. 2014;60:1090–6.
pubmed: 24412603
doi: 10.1016/j.jhep.2013.12.025
Guillot A, Buch C, Jourdan T. Kupffer cell and monocyte-derived macrophage identification by immunofluorescence on formalin-fixed, paraffin-embedded (FFPE) mouse liver sections. In: Aouadi M, Azzimato V (eds). Kupffer cells: methods and protocols. New York, NY: Springer US, 2020, pp 45–53.
Hsieh S-LE, Yang C-Y. CLEC4F, a Kupffer cells specific marker, is critical for presentation of alfa-galactoceromide to NKT cells. J Immunol. 2009;182:78.
doi: 10.4049/jimmunol.182.Supp.78.38
Yang C-Y, Chen J-B, Tsai T-F, Tsai Y-C, Tsai C-Y, Liang P-H, et al. CLEC4F is an inducible C-type lectin in F4/80-positive cells and is involved in alpha-galactosylceramide presentation in liver. PLoS ONE. 2013;8:e65070–e65070.
pubmed: 23762286
pmcid: 3675125
doi: 10.1371/journal.pone.0065070
Yona S, Kim K-W, Wolf Y, Mildner A, Varol D, Breker M, et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013;38:79–91.
pubmed: 23273845
doi: 10.1016/j.immuni.2012.12.001
Borst K, Frenz T, Spanier J, Tegtmeyer P-K, Chhatbar C, Skerra J, et al. Type I interferon receptor signaling delays Kupffer cell replenishment during acute fulminant viral hepatitis. J Hepatol. 2018;68:682–90.
pubmed: 29274730
doi: 10.1016/j.jhep.2017.11.029
Blériot C, Dupuis T, Jouvion G, Eberl G, Disson O, Lecuit M. Liver-resident macrophage necroptosis orchestrates type 1 microbicidal inflammation and type-2-mediated tissue repair during bacterial infection. Immunity. 2015;42:145–58.
pubmed: 25577440
doi: 10.1016/j.immuni.2014.12.020
Devisscher L, Scott CL, Lefere S, Raevens S, Bogaerts E, Paridaens A, et al. Non-alcoholic steatohepatitis induces transient changes within the liver macrophage pool. Cell Immunol. 2017;322:74–83.
pubmed: 29111158
doi: 10.1016/j.cellimm.2017.10.006
Lefere S, Degroote H, Van Vlierberghe H, Devisscher L. Unveiling the depletion of Kupffer cells in experimental hepatocarcinogenesis through liver macrophage subtype-specific markers. J Hepatol. 2019;71:631–3.
pubmed: 31213365
doi: 10.1016/j.jhep.2019.03.016
Zigmond E, Samia-Grinberg S, Pasmanik-Chor M, Brazowski E, Shibolet O, Halpern Z, et al. Infiltrating monocyte-derived macrophages and resident Kupffer cells display different ontogeny and functions in acute liver injury. J Immunol. 2014;193:344–53.
pubmed: 24890723
doi: 10.4049/jimmunol.1400574
Nishiyama K, Nakashima H, Ikarashi M, Kinoshita M, Nakashima M, Aosasa S, et al. Mouse CD11b+Kupffer cells recruited from bone marrow accelerate liver regeneration after partial hepatectomy. PLoS ONE. 2015;10:e0136774.
pubmed: 26333171
pmcid: 4557907
doi: 10.1371/journal.pone.0136774
Reid DT, Reyes JL, McDonald BA, Vo T, Reimer RA, Eksteen B. Kupffer cells undergo fundamental changes during the development of experimental NASH and are critical in initiating liver damage and inflammation. PLoS ONE. 2016;11:e0159524.
pubmed: 27454866
pmcid: 4959686
doi: 10.1371/journal.pone.0159524
Tran S, Baba I, Poupel L, Dussaud S, Moreau M, Gélineau A, et al. Impaired Kupffer cell self-renewal alters the liver response to lipid overload during non-alcoholic steatohepatitis. Immunity. 2020;53:627–40.
pubmed: 32562600
doi: 10.1016/j.immuni.2020.06.003
Elchaninov AV, Fatkhudinov TK, Usman NY, Kananykhina EY, Arutyunyan IV, Makarov AV, et al. Dynamics of macrophage populations of the liver after subtotal hepatectomy in rats. BMC Immunol. 2018;19:23.
pubmed: 29986661
pmcid: 6038314
doi: 10.1186/s12865-018-0260-1
Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology. 2006;43:S45–S53.
pubmed: 16447274
doi: 10.1002/hep.20969
Ichikawa T, Zhang Y-Q, Kogure K, Hasegawa Y, Takagi H, Mori M, et al. Transforming growth factor β and activin tonically inhibit DNA synthesis in the rat liver. Hepatology. 2001;34:918–25.
pubmed: 11679962
doi: 10.1053/jhep.2001.29132
Weglarz TC, Sandgren EP. Timing of hepatocyte entry into DNA synthesis after partial hepatectomy is cell autonomous. Proc Natl Acad Sci USA. 2000;97:12595–12600.
pubmed: 11050176
pmcid: 18809
doi: 10.1073/pnas.220430497
Melgar-Lesmes P, Edelman ER. Monocyte-endothelial cell interactions in the regulation of vascular sprouting and liver regeneration in mouse. J Hepatol. 2015;63:917–25.
pubmed: 26022689
pmcid: 4575901
doi: 10.1016/j.jhep.2015.05.011
Wen Y, Feng D, Wu H, Liu W, Li H, Wang F, et al. Defective initiation of liver regeneration in osteopontin-deficient mice after partial hepatectomy due to insufficient activation of IL-6/Stat3 pathway. Int J Biol Sci. 2015;11:1236–47.
pubmed: 26327817
pmcid: 4551759
doi: 10.7150/ijbs.12118
Shan Z, Ju C. Hepatic macrophages in liver injury. Front Immunol 2020;11:322.
pubmed: 32362892
pmcid: 7180226
doi: 10.3389/fimmu.2020.00322
Abshagen K, Eipel C, Kalff JC, Menger MD, Vollmar B. Loss of NF-κB activation in Kupffer cell-depleted mice impairs liver regeneration after partial hepatectomy. Am J Physiol Liver Physiol. 2007;292:1570–7.
Meijer C, Wiezer MJ, Diehl AM, Yang S-Q, Schouten HJ, Meijer S, et al. Kupffer cell depletion by CI2MDP-liposomes alters hepatic cytokine expression and delays liver regeneration after partial hepatectomy. Liver. 2000;20:66–77.
pubmed: 10726963
doi: 10.1034/j.1600-0676.2000.020001066.x
Böhm F, Köhler UA, Speicher T, Werner S. Regulation of liver regeneration by growth factors and cytokines. EMBO Mol Med. 2010;2:294–305.
pubmed: 20652897
pmcid: 3377328
doi: 10.1002/emmm.201000085
Blindenbacher A, Wang X, Langer I, Savino R, Terracciano L, Heim MH. Interleukin 6 is important for survival after partial hepatectomy in mice. Hepatology. 2003;38:674–82.
pubmed: 12939594
doi: 10.1053/jhep.2003.50378
Schmidt-Arras D, Rose-John S. IL-6 pathway in the liver: from physiopathology to therapy. J Hepatol. 2016;64:1403–15.
pubmed: 26867490
doi: 10.1016/j.jhep.2016.02.004
He Y, Hwang S, Ahmed YA, Feng D, Li N, Ribeiro M, et al. Immunopathobiology and therapeutic targets related to cytokines in liver diseases. Cell Mol Immunol. 2021;18:18–37.
pubmed: 33203939
doi: 10.1038/s41423-020-00580-w
Garbers C, Aparicio-Siegmund S, Rose-John S. The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition. Curr Opin Immunol. 2015;34:75–82.
pubmed: 25749511
doi: 10.1016/j.coi.2015.02.008
Fazel Modares N, Polz R, Haghighi F, Lamertz L, Behnke K, Zhuang Y, et al. IL-6 trans-signaling controls liver regeneration after partial hepatectomy. Hepatology. 2019;70:2075–91.
pubmed: 31100194
doi: 10.1002/hep.30774
Hou X, Yin S, Ren R, Liu S, Yong L, Liu Y et al. Myeloid cell-specific IL-6 signaling promotes miR-223-enriched exosome production to attenuate NAFLD-associated fibrosis. Hepatology. 2020; https://doi.org/10.1002/hep.31658 .
Quintana A, Erta M, Ferrer B, Comes G, Giralt M, Hidalgo J. Astrocyte-specific deficiency of interleukin-6 and its receptor reveal specific roles in survival, body weight and behavior. Brain Behav Immunol. 2013;27:162–73.
doi: 10.1016/j.bbi.2012.10.011
He Y, Feng D, Hwang S, Mackowiak B, Wang X, Xiang X et al. Interleukin-20 exacerbates acute hepatitis and bacterial infection by downregulating Inhibitor of kappa B zeta; target genes in hepatocytes. J Hepatol. 2021. https://doi.org/10.1016/j.jhep.2021.02.004 .
Schug TT, Xu Q, Gao H, Peres-da-Silva A, Draper DW, Fessler MB, et al. Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress. Mol Cell Biol. 2010;30:4712–21.
pubmed: 20647536
pmcid: 2950528
doi: 10.1128/MCB.00657-10
Sun Z, Klein AS, Radaeva S, Hong F, El-Assal O, Pan H, et al. In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats. Gastroenterology. 2003;125:202–15.
pubmed: 12851884
doi: 10.1016/S0016-5085(03)00696-6
Aparicio-Vergara M, Tencerova M, Morgantini C, Barreby E, Aouadi M. Isolation of Kupffer cells and hepatocytes from a single mouse liver BT—alpha-1 antitrypsin deficiency: methods and protocols. In: Borel F, Mueller C (eds). New York, NY: Springer, 2017, pp 161–71.
Jenkins SJ, Ruckerl D, Cook PC, Jones LH, Finkelman FD, van Rooijen N, et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH
pubmed: 21566158
pmcid: 3128495
doi: 10.1126/science.1204351
Wynn AA, Miyakawa K, Miyata E, Dranoff G, Takeya M, Takahashi K. Role of granulocyte/macrophage colony-stimulating factor in zymocel-induced hepatic granuloma formation. Am J Pathol. 2001;158:131–45.
pubmed: 11141486
pmcid: 1850246
doi: 10.1016/S0002-9440(10)63951-X
Kim AR, Park JI, Oh HT, Kim KM, Hwang J-H, Jeong MG, et al. TAZ stimulates liver regeneration through interleukin-6–induced hepatocyte proliferation and inhibition of cell death after liver injury. FASEB J. 2019;33:5914–23.
pubmed: 30742777
doi: 10.1096/fj.201801256RR
Feng D, Dai S, Liu F, Ohtake Y, Zhou Z, Wang H, et al. Cre-inducible human CD59 mediates rapid cell ablation after intermedilysin administration. J Clin Investig. 2016;126:2321–33.
pubmed: 27159394
pmcid: 4887171
doi: 10.1172/JCI84921
Scott CL, Zheng F, De Baetselier P, Martens L, Saeys Y, De Prijck S, et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat Commun. 2016;7:10321.
pubmed: 26813785
pmcid: 4737801
doi: 10.1038/ncomms10321
Vassiliou I, Lolis E, Nastos C, Tympa A, Theodosopoulos T, Dafnios N, et al. The combined effect of erythropoietin and granulocyte macrophage colony stimulating factor on liver regeneration after major hepatectomy in rats. World J Surg Oncol. 2010;8:57.
pubmed: 20604971
pmcid: 2917416
doi: 10.1186/1477-7819-8-57
Liu H-X, Keane R, Sheng L, Wan, JY Y-. Implications of microbiota and bile acid in liver injury and regeneration. J Hepatol. 2015;63:1502–10.
pubmed: 26256437
pmcid: 4654653
doi: 10.1016/j.jhep.2015.08.001
Norris CA, He M, Kang L-I, Ding MQ, Radder JE, Haynes MM, et al. Synthesis of IL-6 by hepatocytes is a normal response to common hepatic stimuli. PLoS ONE. 2014;9:e96053.
pubmed: 24763697
pmcid: 3999098
doi: 10.1371/journal.pone.0096053
Imperatore F, Maurizio J, Vargas Aguilar S, Busch CJ, Favret J, Kowenz-Leutz E, et al. SIRT1 regulates macrophage self-renewal. EMBO J. 2017;36:2353–72.
pubmed: 28701484
pmcid: 5556267
doi: 10.15252/embj.201695737
Jin J, Iakova P, Jiang Y, Medrano EE, Timchenko NA. The reduction of SIRT1 in livers of old mice leads to impaired body homeostasis and to inhibition of liver proliferation. Hepatology. 2011;54:989–98.
pubmed: 21638299
doi: 10.1002/hep.24471
Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16:448–57.
pubmed: 25898198
doi: 10.1038/ni.3153