Molecular mechanisms underlying the protective effect of MIF in experimental liver fibrosis
Year: 2014
Type: dissertation
Abstract: Liver fibrosis, which is the replacement of functional liver tissue with scar tissue, is the characteristic result of all chronic liver diseases. Fibrogenesis is accompanied by inflammation and the activation of hepatic stellate cells (HSCs). These transdifferentiate into myofibroblasts and crucially contribute to the deposition of extracellular matrix and the remodeling of the existing matrix. Unexpectedly, macrophage migration inhibitory factor (MIF), a pleiotropic pro-inflammatory chemokine, attenuated hepatotoxin-induced liver fibrosis in mice. MIF-treated mice showed increases in HSC gene levels, suggesting increased myofibroblast activity following treatment. Leukocyte infiltrates, in contrast, were not affected by MIF treatment. While these data suggest that HSCs mediate MIF-induced protection, the molecular mechanisms underlying its effects have not yet been elucidated. In this work, hepatic cells, including immortalized and primary hepatocytes, Kupffer cells, and HSCs, were characterized as potential cellular sources of hepatic MIF and targets for MIF activity. Hepatocytes release MIF in response to apoptotic and toxic stimuli, while both hepatocytes and Kupffer cells release MIF following oxidative stress. HSCs, however, display a distinct secretion pattern that varies depending on the stimulating pro- or anti-fibrotic cytokine and on the activation status of the cells. Hepatocytes, Kupffer cells, and HSCs express the MIF receptors CD74 and CXCR4 that can localize to the membrane or cytosol depending on the context. These three cell types therefore can provide MIF in response to damage and take part in the reaction to this damage as MIF target cells. Therapeutic application of recombinant MIF in CCl4-induced liver fibrosis reduced the fibrotic response in mice. This further supports the assumption of anti-fibrotic properties of MIF in liver fibrogenesis and emphasizes a role for HSCs in this regulatory mechanism. The MIF/AMPK axis was identified as a relevant signaling pathway mediating anti-fibrotic activity of MIF in myofibroblastic HSCs by inhibiting PDGF-induced proliferation and migration of these cells. Furthermore, the JNK signaling pathway may be involved in the control of HSC behavior by MIF, as it is rapidly activated by MIF in quiescent and activated HSCs. By microarray-based gene expression analysis, this work identified several candidate genes that are differentially regulated in MIF-stimulated HSCs. Some of these may have a functional role in controlling MIF-regulated HSC transdifferentiation and fibrotic activity. The most promising of these candidate genes encodes a so far uncharacterized G protein-coupled receptor. Taken together, this work provides the first insight into the complex regulatory mechanisms by which MIF diminishes the fibrotic response in hepatotoxin-treated mice. A profound understanding of these mechanisms will be fundamental for further approaches that could apply MIF activity in anti-fibrotic therapy.
Source: RWTH Publications (RWTH Aachen)
Authors: Meike Knauel, Jürgen Bernhagen
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1006617008