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Unexpected Pro-Fibrotic Effect of MIF in Non-Alcoholic Steatohepatitis Is Linked to a Shift in NKT Cell Populations

Department of Internal Medicine III, RWTH Aachen University, 52074 Aachen, Germany
Institute of Pathology, RWTH Aachen University, 52074 Aachen, Germany
Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, 52074 Aachen, Germany
Rheumatology Section of the Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8031, USA
Chair of Vascular Biology, Institute of Stroke and Dementia Research, LMU Klinikum, Lud-wig-Maximilian-University (LMU), 81377 Munich, Germany
Munich Cluster for Systems Neurology, 81377 Munich, Germany
Author to whom correspondence should be addressed.
These authors contributed equally to this paper.
Current address: Department of Internal Medicine, Luisenhospital Aachen, 52064 Aachen, Germany.
Academic Editor: Isabel Fabregat
Cells 2021, 10(2), 252;
Received: 23 December 2020 / Revised: 20 January 2021 / Accepted: 22 January 2021 / Published: 28 January 2021
Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine with anti-fibrotic properties in toxic liver injury models and anti-steatotic functions in non-alcoholic fatty liver disease (NAFLD) attributed to the CD74/AMPK signaling pathway. As NAFLD progression is associated with fibrosis, we studied MIF function during NAFLD-associated liver fibrogenesis in mice and men by molecular, histological and immunological methods in vitro and in vivo. After NASH diet feeding, hepatic Mif expression was strongly induced, an effect which was absent in Mifhep mice. In contrast to hepatotoxic fibrosis models, NASH diet-induced fibrogenesis was significantly abrogated in Mif−/− and Mifhep mice associated with a reduced accumulation of the pro-fibrotic type-I NKT cell subpopulation. In vitro, MIF skewed the differentiation of NKT cells towards the type-I subtype. In line with the murine results, expression of fibrosis markers strongly correlated with MIF, its receptors, and markers of NKT type-I cells in NASH patients. We conclude that MIF expression is induced during chronic metabolic injury in mice and men with hepatocytes representing the major source. In NAFLD progression, MIF contributes to liver fibrogenesis skewing NKT cell polarization toward a pro-fibrotic phenotype highlighting the complex, context-dependent role of MIF during chronic liver injury. View Full-Text
Keywords: MIF; NKT cells; NASH; liver fibrosis MIF; NKT cells; NASH; liver fibrosis
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MDPI and ACS Style

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. Unexpected Pro-Fibrotic Effect of MIF in Non-Alcoholic Steatohepatitis Is Linked to a Shift in NKT Cell Populations. Cells 2021, 10, 252.

AMA Style

Heinrichs D, Brandt EF, Fischer P, Köhncke J, Wirtz TH, Guldiken N, Djudjaj S, Boor P, Kroy D, Weiskirchen R, Bucala R, Wasmuth HE, Strnad P, Trautwein C, Bernhagen J, Berres M-L. Unexpected Pro-Fibrotic Effect of MIF in Non-Alcoholic Steatohepatitis Is Linked to a Shift in NKT Cell Populations. Cells. 2021; 10(2):252.

Chicago/Turabian Style

Heinrichs, Daniel, Elisa F. Brandt, Petra Fischer, Janine Köhncke, Theresa H. Wirtz, Nurdan Guldiken, Sonja Djudjaj, Peter Boor, Daniela Kroy, Ralf Weiskirchen, Richard Bucala, Hermann E. Wasmuth, Pavel Strnad, Christian Trautwein, Jürgen Bernhagen, and Marie-Luise Berres. 2021. "Unexpected Pro-Fibrotic Effect of MIF in Non-Alcoholic Steatohepatitis Is Linked to a Shift in NKT Cell Populations" Cells 10, no. 2: 252.

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