SFB 974:  Communication and System Relevance in Liver Injury and Regeneration

• Subject Area: Medicine ; Biology
• Term: from 2012 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 190586431

• Final Report Year: 2021

Final Report Abstract

A number of seminal findings and concepts were recognised and developed within the framework of SFB 974. Hepatic stellate cells (HSC) were for the first time identified as mesenchymal stem cells of the liver, which are involved in liver regeneration by releasing trophic factors and differentiating into epithelial cells. The activation state of the HSC is influenced, among other things, by Reelin, Laminine and embryonic Ras. Furthermore, the space of Disse was for the first time described as a stem cell niche for stellate cells, and Laminin-521 and mechanostress were identified as important elements of this niche. Increased blood flow through the liver leads to the release of angiocrine signals not only from HSC but also from sinusoidal endothelial cells, which induce the proliferation of hepatocytes after partial hepatectomy (PHx) in mice. The absence of the mechanical stimulus after successful proliferation initiates the completion of the regeneration and thus acts as a "hepatostat". The decrease in mechanical stimuli with age could explain the reduced regenerative capacity of the aging liver. β1-integrins act as mechanosensors and mediate the regulation of cell function through changes in cell volume. But they also serve as receptors for taurine-conjugated ursodeoxycholic acid, which is used to treat cholestatic liver diseases. CD169+ cells, which can also produce interleukin 6 (IL-6) are significantly involved in liver regeneration after PHx as well as different macrophage populations. IL-6 trans-signaling via the soluble IL-6 receptor (sIL-6R) induces the expression of the liver growth factor HGF by hepatic stellate cells. IL-6 trans-signaling, but not classical signaling, controls liver regeneration following PHx. The expression of the lymphotoxin-β receptor (LTβR) on hepatocytes, but not on Kupffer cells, is essential for liver regeneration. Functional LTβR/TNFRp55 double deficient mice show complete abrogation of liver regeneration and analysis of these mice revealed so far undescribed LTβR modulated genes important for liver regeneration. Desialyzed platelets and IL-6 mediate increased hepatic thrombopoietin synthesis via the Ashwell-Morell receptor/ IL-6R-JAK2-STAT3 signaling pathway in liver damage. TNF and IL-6 signaling is controlled by ADAM17 and the central cofactor iRhom2. TNF receptors play a central role in viral infections by protecting CD169+ cells, which enable an antiviral immune response through forced virus replication. Bile acids have also been identified as restriction factors for viral infections and can have anti-inflammatory effects. The bile salt receptor TGR5, of which structural models could be created, is important. In biliary epithelial cells, TGR5 is essential for bile salt-dependent cell proliferation, cell protection, and chloride and bicarbonate secretion. TGR5 downregulation aggravates cholestatic liver damage, while TGR5 overexpression is protective. Such overexpression could also be demonstrated in cholangiocarcinoma, which promotes tumor growth. For the molecular study of the two human ABC transporters BSEP (ABCB11) and MDR3 (ABCB4), in vitro systems could be established, e.g. to determine the molecular consequences of disease-relevant mutations in ABCB11. In addition, the transport mechanism of ABCB4 was elucidated. Hepatic encephalopathy (HE), an important extrahepatic disorder in liver diseases, has been identified as a clinical manifestation of a low-grade glial edema with oxidative stress and subsequent disturbance of oscillatory networks in the brain. At the molecular level, ammonia-induced protein modifications such as protein tyrosine nitration and protein O-GlcNAcylation, RNA oxidation, cerebral gene expression changes, TNFR signaling, changes in autophagy and mitophagy as well as metabolic reprogramming through depletion of citrate cycle intermediates play an important role. Liver-specific deletion of glutamine synthetase and knockout of the taurine transporter TauT lead to systemic hyperammonemia. The underlying molecular mechanisms have been identified.

Publications

• (2011) Enforced viral replication activates adaptive immunity and is essential for the control of a cytopathic virus. Nat Immunol. 13(1):51-7
  Honke N, Shaabani N, Cadeddu G, Sorg UR, Zhang DE, Trilling M, Klingel K, Sauter M, Kandolf R, Gailus N, van Rooijen N, Burkart C, Baldus SE, Grusdat M, Löhning M, Hengel H, Pfeffer K, Tanaka M, Häussinger D, Recher M, Lang PA, Lang KS
  
• (2012) iRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS. Science 13;335(6065):229-32
  McIlwain DR, Lang PA, Maretzky T, Hamada K, Ohishi K, Maney SK, Berger T, Murthy A, Duncan G, Xu HC, Lang KS, Häussinger D, Wakeham A, Itie-Youten A, Khokha R, Ohashi PS, Blobel CP, Mak TW
  
• (2013) alpha5 beta1-integrins are sensors for tauroursodeoxycholic acid in hepatocytes. Hepatology 57, 1117-1129
  Gohlke H, Schmitz B, Sommerfeld A, Reinehr R, and Häussinger D
  
• (2013) Gene expression profiling in the cerebral cortex of patients with cirrhosis with and without hepatic encephalopathy. Hepatology 57: 2436-2447
  Görg B, Bidmon HJ, Häussinger D
  
• (2013) Involvement of Toso in activation of monocytes, macrophages and granulocytes. Proc Natl Acad Sci U S A. 110(7):2593-8
  Lang KS, Lang PA, Meryk A, Pandyra AA, Boucher LM, Pozdeev VI, Tusche M, Göthert JR, Haight J, Wakeham D, You-Ten A, McIlwain DR, Merchers K, Khairnar V, Recher M, Nolan GP, Hitoshi Y, Funkner P, Navarini AA, Verschoor A, Shaabani N, Honke N, Penn LZ, Ohashi PS, Häussinger D, Lee KH, Mak TW
  
• (2013) The slowed brain: Cortical oscillatory activity in hepatic encephalopathy. Arch Biochem Biophys. 536: 197-203
  Butz M, May ES, Häussinger D, Schnitzler A
  
• (2014) Hepatic stellate cells contribute to progenitor cells and liver regeneration. J Clin Invest. 124, 5503-5515
  Kordes C, Sawitza I, Götze S, Herebian D, and Häussinger D
  
• (2015) Hyperammonemia in gene-targeted mice lacking functional hepatic glutamine synthetase. Proc Natl Acad Sci U S A. 112, 5521-5526
  Qvartskhava N, Lang PA, Görg B, Pozdeev VI, Ortiz MP, Lang KS, Bidmon HJ, Lang E, Leibrock CB, Herebian D, Bode JG, Lang F, and Häussinger D
  
• (2015) The function of embryonic stem cell-expressed Ras (E-Ras), a unique Ras family member, correlates with its additional motifs and its structural properties. J Biol Chem. 290: 15892-15903
  Nakhaei-Rad S, Nakhaeizadeh H, Cirstea IC, Schmick M, Kordes C, Dvorsky R, Bastiaens PIH, Häussinger D, Ahmadian MR
  
• (2016) Cooperative role of lymphotoxin β receptor and tumor necrosis factor receptor p55 in murine liver regeneration. J Hepatol. 64: 1108-1117
  Sorg UR, Behnke K, Degrandi D, Reich M, Keitel V, Herebian D, Deenen R, Beyer M, Schultze JL, Köhrer K, Gabbert HE, Mayatepek E, Häussinger D, Pfeffer K
  
• (2016) EphrinBs and canonical Reelin signalling. Nature 539(7630):E4-E6
  Pohlkamp T, Xiao L, Sultana R, Bepari A, Bock HH, Henkemeyer M, Herz J
  
• (2016) MAPKAP kinase 2 regulates IL-10 expression and prevents formation of intrahepatic myeloid cell aggregates during cytomegalovirus infections. J Hepatol. 64:380-389
  Ehlting C, Trilling M, Tiedje C, Le-Trilling VTK, Albrecht U, Kluge S, Zimmermann A, Graf D, Gaestel M, Hengel H, Haussinger D, Bode JG
  
• (2016) Molecular mechanisms of glutamine synthetase mutations that lead to clinically relevant pathologies. PLOS Comp Biol. 12, e1004693
  Frieg B, Görg B, Homeyer N, Keitel V, Häussinger D, Gohlke H
  
• (2016) TGR5 is essential for bile acid-dependent cholangiocyte proliferation in vivo and in vitro. Gut 65(3):487-501
  Reich M, Deutschmann K, Sommerfeld A, Klindt C, Kluge S, Kubitz R, Ullmer C, Knoefel WT, Herebian D, Mayatepek E, Häussinger D, Keitel V
  
• (2016) The Role of Embryonic Stem Cell-expressed RAS (ERAS) in the Maintenance of Quiescent Hepatic Stellate Cells. J Biol Chem. 291: 8399-8413
  Nakhaei-Rad S, Nakhaeizadeh H, Götze S, Kordes C, Sawitza I, Hoffmann MJ, Franke M, Schulz WA, Scheller J, Piekorz RP, Häussinger D, Ahmadian MR
  
• (2016) Tumor-necrosis factor impairs CD4(+) T cell-mediated immunological control in chronic viral infection. Nat Immunol. 17(5):593-603
  Beyer M, Abdullah Z, Chemnitz JM, Maisel D, Sander J, Lehmann C, Thabet Y, Shinde PV, Schmidleithner L, Köhne M, Trebicka J, Schierwagen R, Hofmann A, Popov A, Lang KS, Oxenius A, Buch T, Kurts C, Heikenwalder M, Fätkenheuer G, Lang PA, Hartmann P, Knolle PA, Schultze JL
  
• (2017) IL-1β-induced and p38 MAPK-dependent activation of the mitogen-activated protein kinaseactivated protein kinase 2 (MK2) in hepatocytes: Signal transduction with robust and concentration-independent signal amplification. J Biol Chem. 292(15):6291-6302
  Kulawik A, Engesser R, Ehlting C, Raue A, Albrecht U, Hahn B, Lehmann WD, Gaestel M, Klingmüller U, Häussinger D, Timmer J, Bode JG
  
• (2017) Spatiotemporally restricted arenavirus replication induces immune surveillance and type I interferon-dependent tumour regression. Nat Commun. 8:14447
  Kalkavan H, Sharma P, Kasper S, Helfrich I, Pandyra AA, Gassa A, Virchow I, Flatz L, Brandenburg T, Namineni S, Heikenwalder M, Höchst B, Knolle PA, Wollmann G, von Laer D, Drexler I, Rathbun J, Cannon PM, Scheu S, Bauer J, Chauhan J, Häussinger D, Willimsky G, Löhning M, Schadendorf D, Brandau S, Schuler M, Lang PA, Lang KS
  
• (2018) B Cell-Mediated Maintenance of Cluster of Differentiation 169-Positive Cells Is Critical for Liver Regeneration. Hepatology 68(6):2348-2361
  Behnke K, Zhuang Y, Xu HC, Sundaram B, Reich M, Shinde PV, Huang J, Modares NF, Tumanov AV, Polz R, Scheller J, Ware CF, Pfeffer K, Keitel V, Häussinger D, Pandyra AA, Lang KS, Lang PA
  
• (2018) Laminin-521 promotes quiescence in isolated stellate cells from rat liver. Biomaterials 180:36-51
  Rohn F, Kordes C, Castoldi M, Götze S, Poschmann G, Stühler K, Herebian D, Benk AS, Geiger F, Zhang T, Spatz JP, Häussinger D
  
• (2018) Mechanosensing by β1 integrin induces angiocrine signals for liver growth and survival. Nature 562(7725):128-132
  Lorenz L, Axnick J, Buschmann T, Henning C, Urner S, Fang S, Nurmi H, Eichhorst N, Holtmeier R, Bódis K, Hwang JH, Müssig K, Eberhard D, Stypmann J, Kuss O, Roden M, Alitalo K, Häussinger D, Lammert E
  
• (2018) Soluble gp130 prevents interleukin-6 and interleukin-11 cluster signaling but not intracellular autocrine responses. Sci Signal. 11(550):eaar7388
  Lamertz L, Rummel F, Polz R, Baran P, Hansen S, Waetzig GH, Moll JM, Floss DM, Scheller J
  
• (2018) Synthetic cytokine receptors transmit biological signals using artificial ligands. Nat Commun. 9(1):2034
  Engelowski E, Schneider A, Franke M, Xu H, Clemen R, Lang A, Baran P, Binsch C, Knebel B, Al-Hasani H, Moll JM, Floß DM, Lang PA, Scheller J
  
• (2019) Biallelic mutation of human SLC6A6 encoding the taurine transporter TAUT is linked to early retinal degeneration. FASEB J. 33:11507-11527
  Preising MN, Görg B, Friedburg C, Qvartskhava N, Budde BS, Bonus M, Toliat MR, Pfleger C, Altmüller J, Herebian D, Beyer M, Zöllner HJ, Wittsack HJ, Schaper J, Klee D, Zechner U, Nürnberg P, Schipper J, Schnitzler A, Gohlke H, Lorenz B, Häussinger D, Bolz HJ
  
• (2019) CD8(+) T cells induce cachexia during chronic viral infection. Nat Immunol. 20:701-710
  Baazim H, Schweiger M, Moschinger M, Xu H, Scherer T, Popa A, Gallage S, Ali A, Khamina K, Kosack L, Vilagos B, Smyth M, Lercher A, Friske J, Merkler D, Aderem A, Helbich TH, Heikenwalder M, Lang PA, Zechner R, Bergthaler A
  
• (2019) Chemical exchange saturation transfer imaging in hepatic encephalopathy. Neuroimage Clin. 22: 101743
  Zöllner HJ, Butz M, Jördens M, Füllenbach ND, Häussinger D, Schmitt B, Wittsack HJ, Schnitzler A
  
• (2019) Cooperative and distinct functions of MK2 and MK3 in the regulation of the macrophage transcriptional response to lipopolysaccharide. Sci Rep. 9(1):11021
  Ehlting C, Rex J, Albrecht U, Deenen R, Tiedje C, Köhrer K, Sawodny O, Gaestel M, Häussinger D, Bode JG
  
• (2019) IL-6 Trans-signaling Controls Liver Regeneration After Partial Hepatectomy. Hepatology 70(6):2075-2091
  Fazel Modares N, Polz R, Haghighi F, Lamertz L, Behnke K, Zhuang Y, Kordes C, Häussinger D, Sorg UR, Pfeffer K, Floss DM, Moll JM, Piekorz RP, Ahmadian MR, Lang PA, Scheller J
  
• (2019) O-GlcNAcylation-dependent upregulation of HO1 triggers ammonia-induced oxidative stress and senescence in hepatic encephalopathy. J Hepatol. 71: 930-941
  Görg B, Karababa A, Schutz E, Paluschinski M, Schrimpf A, Shafigullina A, Castoldi M, Bidmon HJ, Häussinger D
  
• (2019) Phosphorylated tyrosine 93 of hepatitis C virus nonstructural protein 5A is essential for interaction with host c-Src and efficient viral replication. J Biol Chem 294: 7388-7402
  Klinker S, Stindt S, Gremer L, Bode JG, Gertzen CGW, Gohlke H, Weiergraber OH, Hoffmann S, Willbold D
  
• (2019) Taurine transporter (TauT) deficiency impairs ammonia detoxification in mouse liver. Proc Natl Acad Sci U S A. 116: 6313-6318
  Qvartskhava N, Jin CJ, Buschmann T, Albrecht U, Bode JG, Monhasery N, Oenarto J, Bidmon HJ, Görg B, Häussinger D
  
• (2020) A dual role for hepatocyte-intrinsic canonical NF-κB signaling in virus control. J Hepatol. 72:960-975
  Namineni S, O'Connor T, Faure-Dupuy S, Johansen P, Riedl T, Liu K, Xu H, Singh I, Shinde P, Li F, Pandyra A, Sharma P, Ringelhan M, Muschaweckh A, Borst K, Blank P, Lampl S, Neuhaus K, Durantel D, Farhat R, Weber A, Lenggenhager D, Kündig TM, Staeheli P, Protzer U, Wohlleber D, Holzmann B, Binder M, Breuhahn K, Assmus LM, Nattermann J, Abdullah Z, Rolland M, Dejardin E, Lang PA, Lang KS, Karin M, Lucifora J, Kalinke U, Knolle PA, Heikenwalder M
  
• (2020) Ammonia inhibits energy metabolism in astrocytes in a rapid and glutamate dehydrogenase 2-dependent manner. Dis Model Mech. 13
  Drews L, Zimmermann M, Westhoff P, Brilhaus D, Poss RE, Bergmann L, Wiek C, Brenneisen P, Piekorz RP, Mettler-Altmann T, Weber APM, Reichert AS
  
• (2020) Cristae undergo continuous cycles of membrane remodelling in a MICOS-dependent manner. EMBO Rep. 21(3):e49776
  Kondadi AK, Anand R, Hansch S, Urbach J, Zobel T, Wolf DM, Segawa M, Liesa M, Shirihai OS, Weidtkamp-Peters S, Reichert AS
  
• (2020) Efficiently restored thrombopoietin production via AMR and IL-6R induced JAK2-STAT3 signaling early after partial hepatectomy. Hepatology
  Reusswig F, Modares NF, Brechtenkamp M, Wienands L, Krüger I, Behnke K, Lee-Sundlov MM, Herebian D, Scheller J, Hoffmeister KM, Häussinger D, Elvers M
  
• (2020) Evidence for functional selectivity in TUDC- and norUDCA-induced signal transduction via α5β1 integrin towards choleresis. Sci Rep. 10, 5795
  Bonus M, Sommerfeld A, Qvartskhava N, Görg B, Ludwig BS, Kessler H, Gohlke H, Häussinger D
  
• (2020) Impaired integrin α5/β1-mediated hepatocyte growth factor release by stellate cells of the aged liver. Aging Cell. 19(4):e13131
  Rohn F, Kordes C, Buschmann T, Reichert D, Wammers M, Poschmann G, Stühler K, Benk AS, Geiger F, Spatz JP, Häussinger D
  
• (2020) Stimulation of ABCB4/MDR3 ATPase activity requires an intact phosphatidylcholine lipid. J Lip Res. 61(12):1605-1616
  Prescher M, Smits SHJ, Schmitt L
  
• (2021) Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis. J Hepatol. 16;S0168-8278(21)00244-0
  Reich M, Spomer L, Klindt C, Fuchs K, Stindt J, Deutschmann K, Höhne J, Liaskou E, Hov JR, Karlsen TH, Beuers U, Verheij J, Ferreira-Gonzalez S, Hirschfield G, Forbes SJ, Schramm C, Esposito I, Nierhoff D, Fickert P, Fuchs CD, Trauner M, García-Beccaria M, Gabernet G, Nahnsen S, Mallm JP, Vogel M, Schoonjans K, Lautwein T, Köhrer K, Häussinger D, Luedde T, Heikenwalder M, Keitel V
  
• (2021) Structure and function of hepatobiliary ATP Binding Cassette Transporters. Chem Rev. 121(9):5240-5288
  Kroll T, Prescher M, Smits SHJ, Schmitt, L