P07 PD Dr. Berres/Prof. Dr. Bernhagen
Targeting MIF family proteins in liver fibrosis: Mechanisms and translational approaches

MIF is a chemokine-like inflammatory cytokine interacting with CD74/Ii and the chemokine receptors CXCR2/4. In the previous funding periods, we surprisingly unravelled a mechanistically multi-layered, context-dependent role of MIF in liver injury, encompassing CD74/AMPK-dependent hepatoprotection in toxin-triggered fibrogenesis and fatty liver disease, whereas fibrosis was reduced upon Mif deletion in a NASH model. Here, we study the emerging networks and novel molecular players in the MIF protein/receptor family (MIF-2, CXCR7, TIMP-1) and characterize their role in liver fibrogenesis of different aetiologies in experimental settings and translational approaches. [...]

Publications

• Heinrichs D. , Brandt E. F., Fischer P., Köhncke J., Wirtz T. H., Guldiken N., Djudjaj S., Boor P., Kroy D., Weiskirchen R., Bucala R., Wasmuth H. E., Strnad P., Trautwein C., Bernhagen J., Berres M.-L. (2021): Unexpected Pro-Fibrotic Effect of MIF in Non-Alcoholic Steatohepatitis Is Linked to a Shift in NKT Cell Populations. Cells, in press, [5.656]
• Wirtz T. H. , Reuken P. A., Jansen C., Fischer P., Bergmann I., Backhaus C., Emontzpohl C., Reißing J., Brandt E. F., Koenen T. M., Schneider K. M., Schierwagen R., Brol M. J., Chang J., Zimmermann H. W., Köse-Vogel N., Eggermann T., Kurth I., Stoppe C., Bucala R., Bernhagen J., Praktiknjo M., Stallmach A., Trautwein C., Trebicka J., Bruns T., Berres M.-L. (2021): Balance between macrophage migration inhibitory factor and sCD74 predicts outcome in patients with acute decompensation of cirrhosis. JHEP Reports, in press,
• Wirtz T. H. , Fischer P., Backhaus C., Bergmann I., Brandt E. F., Heinrichs D., Koenen M. T., Schneider K. M., Eggermann T., Kurth I., Stoppe C., Bernhagen J., Bruns T., Fischer J., Berg T., Trautwein C., Berres M.-L. 1 (2019): Genetic Variants in the Promoter Region of the Macrophage Migration Inhibitory Factor are Associated with the Severity of Hepatitis C Virus-Induced Liver Fibrosis. Internation Journal of Molecular Sciences, 20(15), 3753, [3.687]
• Wirtz T. H. , Brandt E. F., Berres M. L. (2019): Liver DCs in health and disease. International Review of Cell & Molecular biology (IRCMB), 348, 263-299, [3.788]
• Jordan S. , Tung N., Casanova-Acebes M., Chang C., Cantoni C., Zhang D., Wirtz T. H., Naik S., Rose S. A., Brocker C. N., Gainullina A., Hornburg D., Horng S., Maier B. B., Cravedi P., LeRoith D., Gonzalez F. J., Meissner F., Ochando J., Rahman A., Chipuk J. E., Artyomov M. N., Frenette P. S., Piccio L., Berres M. L., Gallagher E. J., Merad M. (2019): Dietary Intake Regulates the Circulating Inflammatory Monocyte Pool. Cell, 178(5), 1102-1114, [36.216]
• Drescher H. K. , Brandt E. F., Fischer P., Dreschers S., Schwendener R. A., Kowalska M. A., Canbay A., Wasmuth H. E., Weiskirchen R., Trautwein C., Berres M. L., Kroy D. C., Sahin H. (2019): “.” 10, 326, [3.201] (2019): Platelet Factor 4 Attenuates Experimental Acute Liver Injury in Mice. Front Physiol, 10, 326, [3.201]
• Lehmann J. M. , Claus K., Jansen C., Pohlmann A., Schierwagen R., Meyer C., Thomas D., Manekeller S., Claria J., Strassburg C. P., Trautwein C., Wasmuth H. E., Berres M. L., Trebicka J. (2018): Circulating CXCL10 in cirrhotic portal hypertension might reflect systemic inflammation and predict ACLF and mortality. Liver Int, 38(5), 875-884, [5.542]
• Hogstad B. , Berres M. L., Chakraborty R., Tang J., Bigenwald C., Serasinghe M., Lim K. P. H., Lin H., Man T. K., Remark R., Baxter S., Kana V., Jordan S., Karoulia Z., Kwan W. H., Leboeuf M., Brandt E., Salmon H., McClain K., Poulikakos P., Chipuk J., Mulder W. J. M., Allen C. E., Merad M. (2018): RAF/MEK/extracellular signal-related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions. Exp Med, 215(1), 319-336, [10.829]
• Djudjaj, S. , Martin, I.V., Buhl, E.M., Nothofer, N.J., Leng, L., Piecychna, M., Floege, J., Bernhagen, J., Bucala, R., Boor, P. (2017): Macrophage Migration Inhibitory Factor limits renal Inflammation and fibrosis by counteracting tubular cell cycle arrest. Journal of the American Society of Nephrology, 28 (12), [8.491]
• Berres M.L. , Lehmann J, Jansen C, Görtzen J, Meyer C, Thomas D, Zimmermann HW, Kroy D, Schumacher F, Strassburg CP, Sauerbruch T, Trautwein C, Wasmuth HE, Trebicka J. (2016): Chemokine (C-X-C motif) ligand 11 levels predict survival in cirrhotic patients with transjugular intrahepatic portosystemic shunt. Liver Int., Mar, 36(3):386-94. doi: 10.1111/liv.12922. Epub 2015 Aug 17. PubMed PMID: 26212075., [4.470]
• Pawig, L. , Klasen, C., Weber, C., Bernhagen, J., Noels, H. (2015): Diversity and Inter-Connections in the CXCR4 Chemokine Receptor/Ligand Family: Molecular Perspectives.. Front Immunol, 6, 429, [5.695]
• Panstruga, R. (2015): Phylogeny and evolution of plant macrophage migration inhibitory factor/D-dopachrome tautomerase-like proteins.. BMC Evol Biol, [3.406]
• Kim, B. S. , Pallua, N., Bernhagen, J., Bucala, R. (2015): The macrophage migration inhibitory factor protein superfamily in obesity and wound repair.. Experimental & Molecular Medicine, 47 e161, [5.164]
• Heinrichs, D. , Berres, M. L., Coeuru, M., Knauel, M., Nellen, A., Fischer, P., Philippeit, C., Bucala, R., Trautwein, C., Wasmuth, H. E., Bernhagen, J. (2015): Protective role of macrophage migration inhibitory factor in nonalcoholic steatohepatitis.. FASEB J, 28(12), 5136-5147, [5.040]
• Dickerhof, N. (2015): Macrophage migration inhibitory factor (MIF) is rendered enzymatically inactive by myeloperoxidase-derived oxidants but retains its immunomodulatory function.. Free Radical Biol Med, [5.740]
• Berres, M. L. , Lehmann, J., Jansen, C., Görtzen, J., Meyer, C., Thomas, D., Zimmermann, H. W., Kroy, D., Schuhmacher, F., Strassburg, C. P., Sauerbruch, T., Trautwein, C., Wasmuth, H. E., Trebicka, J. (2015): Chemokine (C-X-C motif) ligand 11 levels predict survival in cirrhotic patients with transjugular intrahepatic portosystemic shunt.. Liver Int, Mar;36(3), 386-94, [4.850]
• Berres, M. L. , Asmacher, S. S., Lehmann, J., Jansen, C., Görtzen, J., Klein, S., Meyer, C., Strunk, H. M., Fimmers, R., Tacke, F., Strassburg, C. P., Trautwein, C., Sauerbruch, T., Wasmuth, H. E., Trebicka (2015): CXCL9 is a prognostic marker in patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt.. J Hepatol, 62(2), 332-339, [11.370]
• Moeller, M.J , Kuppe C. (2014): Glomerular disease: the role of parietal epithelial cells in hyperplastic lesions. Nature Reviews Nephrology, 10(11), 615-6, [9.463]
• Kraemer, S. , Alampour-Rajabi, S., El Bounkari, O., Bernhagen, J. (2014): Hetero-oligomerization of chemokine receptors: diversity and relevance for function. Current Medicinal Chemistry, 20, 2524-2536, [3.455]
• Berres, M. L. (2014): Progress in understanding the pathogenesis of Langerhans cell histiocytosis: back to Histiocytosis X?. British Journal of Haematology, 169 (1), 3-13, [5.812]
• Assis, D. N. , Leng, L., Du, X., Zhang, C. K., Grieb, G., Merk, M., Garcia, A. B., McCrann, C., Chapiro, J., Meinhardt, A., Mizue, Y., Nikolic-Paterson, D. J., Bernhagen, J., Kaplan, M. M., Zhao, H., Boyer, J. L., Bucala, R. (2014): The role of macrophage migration inhibitory factor in autoimmune liver disease.. Hepatology, 59(2), 580-591, [11.711]
• Sobierajski, J. , Hendgen-Cotta, U. B., Luedike, P., Stock, P., Rammos, C., Meyer, C., Kraemer, S., Stoppe, C., Bernhagen, J., Kelm, M., Rassaf, T. (2013): Assessment of macrophage migration inhibitory factor in humans: protocol for accurate and reproducible levels.. Free Radical Biology and Medicine, 63, 236-242, [5.784]
• Strüßmann, T. , Tillmann, S., Wirtz, T., Bucala, R., von Hundelshausen, P., Bernhagen, J. (2013): Platelets are a previously unrecognised source of MIF.. Thromb Haemost, 110(5), 1004-1013, [5.565]
• Kellner, P. , Anadol, E., Huneburg, R., Hundt, F., Bos, D., Klein, B., Woitas, R. P., Spengler, U., Sauerbruch, T., Trebicka, J. (2013): The effect of hemodialysis on liver stiffness measurement: a single-center series.. European Journal of Gastroenterol & Hepatology, 25 (3), 368-372, [2.093]
• Sahin, H. , Borkham-Kamphorst, E., do, O. N., Berres, M. L., Kaldenbach, M., Schmitz, P., Weiskirchen, R., Liedtke, C., Streetz, K. L., Maedler, K., Trautwein, C., Wasmuth, H. E. (2013): Proapoptotic effects of the chemokine, CXCL 10 are mediated by the noncognate receptor TLR4 in hepatocytes.. Hepatology, 57 (2), 797-805, [11.711]
• Schwartz, V. , Kruttgen, A., Weis, J., Weber, C., Ostendorf, T., Lue, H., Bernhagen, J. (2012): Role for CD74 and CXCR4 in clathrin-dependent endocytosis of the cytokine MIF. European Journal of Cell Biology, 91, 435-449, [4.011]
• Luedike, P. , Hendgen-Cotta, U. B., Sobierajski, J., Totzeck, M., Reeh, M., Dewor, M., Lue, H., Krisp, C., Wolters, D., Kelm, M., Bernhagen, J., Rassaf, T. (2012): Cardioprotection Through S-Nitros(yl)ation of Macrophage Migration Inhibitory Factor. Circulation, 125, 1880-1889, [17.202]
• Kraemer, S. , Weber, C., Bernhagen, J. (2012): The MIF Handbook. 2, [6.085]
• Bounkari, O. E. , Bernhagen, J. (2012): MIF and autophagy: a novel link beyond "eating". Cell Research, 22, 950-953, [14.812]
• Sahin, H. , Borkham-Kamphorst, E., Kuppe, C., Zaldivar, M. M., Grouls, C., Al-Samman, M., Nellen, A., Schmitz, P., Heinrichs, D., Berres, M. L., Doleschel, D., Scholten, D., Weiskirchen, R., Moeller, M. J., Kiessling, F., Trautwein, C., Wasmuth, H. E. (2012): Chemokine Cxcl9 attenuates liver fibrosis-associated angiogenesis in mice. Hepatology, 55 (5), 1610-1619, [11.711]
• Merk, M. , Zierow, S., Leng, L., Das, R., Du, X., Schulte, W., Fan, J., Lue, H., Chen, Y., Xiong, H., Chagnon, F., Bernhagen, J., Lolis, E., Mor, G., Lesur, O., Bucala, R. (2011): The D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF). Proceedings of the National Academy of Sciences of the U S A, 108 (34), 577-585, [9.423]
• Lue, H. , Dewor, M., Leng, L., Bucala, R., Bernhagen, J. (2011): Activation of the JNK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on CXCR4 and CD74. Cellular Signalling, 23 (1), 135-144, [4.191]
• Tacke, F. , Zimmermann, H. W., Berres, M. L., Trautwein, C., Wasmuth, H. E. (2011): Serum chemokine receptor CXCR3 ligands are associated with progression, organ dysfunction and complications of chronic liver diseases. Liver International, 31 (6), 840-849, [4.470]
• Moleda, L. , Trebicka, J., Dietrich, P., Gabele, E., Hellerbrand, C., Straub, R. H., Sauerbruch, T., Schoelmerich, J., Wiest, R. (2011): Amelioration of portal hypertension and the hyperdynamic circulatory syndrome in cirrhotic rats by neuropeptide Y via pronounced splanchnic vasoaction. Gut, 60, 1122-1132, [14.921]
• Lettow, I. , Berres, M. L., Schmitz, P., Muller, T., Berg, T., Neumann, U. P., Trautwein, C., Wasmuth, H. E. (2011): A Duffy antigen receptor for chemokines (DARC) polymorphism that determines pro-fibrotic chemokine serum concentrations is not directly associated with severity of hepatitis C infection. Human Immunology, 72 (3), 273-277, [2.127]
• Heinrichs, D. , Knauel, M., Offermanns, C., Berres, M. L., Nellen, A., Leng, L., Schmitz, P., Bucala, R., Trautwein, C., Weber, C., Bernhagen, J., Wasmuth, H. E. (2011): Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74. Proceedings of the National Academy of Sciences of the U S A, 108 (42), 17444-17449, [9.423]
• Berres, M. L. , Trautwein, C., Schmeding, M., Eurich, D., Tacke, F., Bahra, M., Neuhaus, P., Neumann, U. P., Wasmuth, H. E. (2011): Serum chemokine CXC ligand 10 (CXCL10) predicts fibrosis progression after liver transplantation for hepatitis C infection. Hepatology, 53 (2), 596-603, [11.711]
• Ma, H. , Wang, J., Thomas, D. P., Tong, C., Leng, L., Wang, W., Merk, M., Zierow, S., Bernhagen, J., Ren, J., Bucala, R., Li, J. (2010): Impaired macrophage migration inhibitory factor-AMP-activated protein kinase activation and ischemic recovery in the senescent heart. Circulation, 122 (3), 282-292, [17.202]
• Zaldivar, M. M. , Pauels, K., von Hundelshausen, P., Berres, M. L., Schmitz, P., Bornemann, J., Kowalska, M. A., Gassler, N., Streetz, K. L., Weiskirchen, R., Trautwein, C., Weber, C., Wasmuth, H. E. (2010): CXC chemokine ligand 4 (Cxcl4) is a platelet-derived mediator of experimental liver fibrosis. Hepatology, 51 (4), 1345-1353, [11.711]
• Bettermann, K. , Vucur, M., Haybaeck, J., Koppe, C., Janssen, J., Heymann, F., Weber, A., Weiskirchen, R., Liedtke, C., Gassler, N., Muller, M., de Vos, R., Wolf, M. J., Boege, Y., Seleznik, G. M., Zeller, N., Erny, D., Fuchs, T., Zoller, S., Cairo, S., Buendia, M. A., Prinz, M., Akira, S., Tacke, F., Heikenwalder, M., Trautwein, C., Luedde, T. (2010): TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer. Cancer Cell, 17 (5), 481-496, [23.214]
• Berres, M. L. , Koenen, R. R., Rueland, A., Zaldivar, M. M., Heinrichs, D., Sahin, H., Schmitz, P., Streetz, K. L., Berg, T., Gassler, N., Weiskirchen, R., Proudfoot, A., Weber, C., Trautwein, C., Wasmuth, H. E. (2010): Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice. Journal of Clinical Investigation, 120 (11), 4129-4140, [12.575]
• Wasmuth, H. E. , Lammert, F., Zaldivar, M. M., Weiskirchen, R., Hellerbrand, C., Scholten, D., Berres, M. L., Zimmermann, H., Streetz, K. L., Tacke, F., Hillebrandt, S., Schmitz, P., Keppeler, H., Berg, T., Dahl, E., Gassler, N., Friedman, S. L., Trautwein, C. (2009): Antifibrotic effects of CXCL9 and its receptor CXCR3 in livers of mice and humans.. Gastroenterology, 137, 309-319, 301-303, [18.187]
• Berres, M. L. , Trautwein, C., Zaldivar, M. M., Schmitz, P., Pauels, K., Lira, S. A., Tacke, F., Wasmuth, H. E. (2009): The chemokine scavenging receptor D6 limits acute toxic liver injury in vivo. Biol Chem, 390, 1039-1045, [2.710]