Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-10, Vol.108 (42), p.17444-17449
• Main Authors: Heinrichs, Daniel, Knauel, Meike, Offermanns, Christian, Berres, Marie-Luise, Nellen, Andreas, Leng, Lin, Schmitz, Petra, Bucala, Richard, Trautwein, Christian, Weber, Christian, Bernhagen, Jürgen, Wasmuth, Hermann E
• Format: Article
• Language: English
• Subjects: AMP-activated protein kinase; AMP-Activated Protein Kinases - metabolism; Animal models; Animals; Antibodies; Antigens, Differentiation, B-Lymphocyte - genetics; Antigens, Differentiation, B-Lymphocyte - physiology; Biological Sciences; Carbon Tetrachloride - toxicity; Cell lines; Cell proliferation; Cytokines; Fibrosis; Gene Expression; genes; Hepatic stellate cells; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - pathology; Hepatic Stellate Cells - physiology; Histocompatibility Antigens Class II - genetics; Histocompatibility Antigens Class II - physiology; Inflammation; Inflammatory diseases; Injuries; Intramolecular Oxidoreductases - deficiency; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - pharmacology; Intramolecular Oxidoreductases - physiology; Kinases; Leukocyte migration; Liver; liver cirrhosis; Liver Cirrhosis, Experimental - drug therapy; Liver Cirrhosis, Experimental - etiology; Liver Cirrhosis, Experimental - pathology; Liver Cirrhosis, Experimental - physiopathology; Liver diseases; Macrophage migration inhibitory factor; Macrophage Migration-Inhibitory Factors - deficiency; Macrophage Migration-Inhibitory Factors - genetics; Macrophage Migration-Inhibitory Factors - pharmacology; Macrophage Migration-Inhibitory Factors - physiology; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Morbidity; Phosphorylation; Physical trauma; Platelet-Derived Growth Factor - pharmacology; Receptors; Recombinant Proteins - pharmacology; Rodents; Signal Transduction; stellate cells
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1107023108

Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine that has been implicated in various inflammatory diseases. Chronic inflammation is a mainstay of liver fibrosis, a leading cause of morbidity worldwide, but the role of MIF in liver scarring has not yet been elucidated. Here we have uncovered an unexpected antifibrotic role for MIF. Mice genetically deleted in Mif (Mif–/–) showed strongly increased fibrosis in two models of chronic liver injury. Pronounced liver fibrosis in Mif–/– mice was associated with alterations in fibrosis-relevant genes, but not by a changed intrahepatic immune cell infiltration. Next, a direct impact of MIF on hepatic stellate cells (HSC) was assessed in vitro. Although MIF alone had only marginal effects on HSCs, it markedly inhibited PDGF-induced migration and proliferation of these cells. The inhibitory effects of MIF were mediated by CD74, which we detected as the most abundant known MIF receptor on HSCs. MIF promoted the phosphorylation of AMP-activated protein kinase (AMPK) in a CD74-dependent manner and, in turn, inhibition of AMPK reversed the inhibition of PDGF-induced HSC activation by MIF. The pivotal role of CD74 in MIF-mediated antifibrotic properties was further supported by augmented liver scarring of Cd74–/– mice. Moreover, mice treated with recombinant MIF displayed a reduced fibrogenic response in vivo. In conclusion, we describe a previously unexplored antifibrotic function of MIF that is mediated by the CD74/AMPK signaling pathway in HSCs. The results imply MIF and CD74 as targets for treatment of liver diseases.