Abstract
BackgroundMacrophages play critical roles in liver regeneration, fibrosis development and resolution. They are among the first responders to liver injury and are implicated in orchestrating the fibrogenic response via multiple mechanisms. Macrophages are also intimately associated with the activated hepatic progenitor cell (HPC) niche or ductular reaction that develops in parallel with fibrosis. Among the many macrophage-derived mediators implicated in liver disease progression, a key role for macrophage-derived Wnt proteins in driving pro-regenerative HPC activation towards a hepatocellular fate has been suggested. Wnt proteins, in general, however, have been associated with both pro- and anti-fibrogenic activities in the liver and other organs. We investigated the role of macrophage-derived Wnt proteins in fibrogenesis and HPC activation in murine models of chronic liver disease by conditionally deleting Wntless expression, which encodes a chaperone essential for Wnt protein secretion, in LysM-Cre-expressing myeloid cells (LysM-Wls mice).ResultsFibrosis and HPC activation were exacerbated in LysM-Wls mice compared to littermate controls, in the absence of an apparent increase in myofibroblast activation or interstitial collagen mRNA expression, in both the TAA and CDE models of chronic liver disease. Increased Epcam mRNA levels paralleled the increased HPC activation and more mature ductular reactions, in LysM-Wls mice. Increased Epcam expression in LysM-Wls HPC was also observed, consistent with a more cholangiocytic phenotype. No differences in the mRNA expression levels of key pro-inflammatory and pro-fibrotic cytokines or the macrophage-derived HPC mitogen, Tweak, were observed. LysM-Wls mice exhibited increased expression of Timp1, encoding the key Mmp inhibitor Timp1 that blocks interstitial collagen degradation, and, in the TAA model, reduced expression of the anti-fibrotic matrix metalloproteinases, Mmp12 and Mmp13, suggesting a role for macrophage-derived Wnt proteins in restraining fibrogenesis during ongoing liver injury.ConclusionIn summary, these data suggest that macrophage-derived Wnt proteins possess anti-fibrogenic potential in chronic liver disease, which may be able to be manipulated for therapeutic benefit.Electronic supplementary materialThe online version of this article (doi:10.1186/s13069-015-0036-7) contains supplementary material, which is available to authorized users.
Highlights
Macrophages play critical roles in liver regeneration, fibrosis development and resolution
We investigated the contribution of macrophage-derived Wnt proteins (Wnts) to hepatic progenitor cell (HPC) activation and fibrogenesis during chronic liver disease
Myeloid-specific Wls knockout does not affect liver macrophage abundance or localisation To investigate the contribution of macrophage-derived Wnt proteins to inflammation, HPC activation and fibrosis, we generated mice deficient in Wls expression in myeloid cells by crossing Wls-loxp mice [40] with LysM-Cre mice [41] for 4–10 generations
Summary
Macrophages play critical roles in liver regeneration, fibrosis development and resolution They are among the first responders to liver injury and are implicated in orchestrating the fibrogenic response via multiple mechanisms. We investigated the role of macrophage-derived Wnt proteins in fibrogenesis and HPC activation in murine models of chronic liver disease by conditionally deleting Wntless expression, which encodes a chaperone essential for Wnt protein secretion, in LysM-Cre-expressing myeloid cells (LysM-Wls mice). Regardless of their aetiology, chronic liver diseases (CLDs) share a common pathological mechanism, liver-injury stimulated fibrosis, which, if progressive, can lead to cirrhosis, liver failure, and cancer. With no therapies available to prevent or treat liver fibrosis, better understanding of the mechanisms of fibrosis and repair and the role of inflammatory cells and mediators is crucial to developing new therapeutic approaches
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