Abstract
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 Mif∆hep mice. In contrast to hepatotoxic fibrosis models, NASH diet-induced fibrogenesis was significantly abrogated in Mif−/− and Mif∆hep 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.
Highlights
WT mice subjected to a methionine- and choline-deficient diet (MCD) for eight weeks and mice on standard chow (SC)
To verify if migration inhibitory factor (MIF) induction during NASH progression is conserved across species, we analyzed intrahepatic MIF expression in a cohort of 22 patients comprising the broad spectrum of NASH from simple steatosis to advanced NASH-associated fibrosis
Theand ameliorated fibrosis phenotype could be observed in mice selectively liver fibrosis high fat diet-induced fatty liver degeneration
Summary
Chronic liver diseases are a common health burden worldwide resulting in fibrosis and consecutive cirrhosis [1]. Chronic liver injuries thereby initiate an inflammatory response, which triggers the trans-differentiation of hepatic stellate cells (HSCs) from a quiescent vitamin A-storing phenotype into a highly activated state. Activated stellate cells produce an excess of extracellular matrix proteins leading to excessive scarring and fibrogenesis [2,3]. The inflammatory response elicits the recruitment and accumulation of immune cell populations such as monocytes/macrophages, T cells, natural killer (NK)
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