Title: Hepatic stellate cells orchestrate clearance of necrotic cells in a hypoxia-inducible factor-1α-dependent manner by modulating macrophage phenotype in mice.

Authors: Mochizuki, Akie; Pace, Aaron; Rockwell, Cheryl E; Roth, Katherine J; Chow, Aaron; O'Brien, Kate M; Albee, Ryan; Kelly, Kara; Towery, Keara; Luyendyk, James P; Copple, Bryan L

Published In J Immunol, (2014 Apr 15)

Abstract: Hypoxia-inducible factor-1α (HIF-1α) is activated in hepatic stellate cells (HSCs) by hypoxia and regulates genes important for tissue repair. Whether HIF-1α is activated in HSCs after acute injury and contributes to liver regeneration, however, is not known. To investigate this, mice were generated with reduced levels of HIF-1α in HSCs by crossing HIF-1α floxed mice with mice that express Cre recombinase under control of the glial fibrillary acidic protein (GFAP) promoter (i.e., HIF-1α-GFAP Cre+ mice). These mice and control mice (i.e., HIF-1α-GFAP Cre- mice) were treated with a single dose of carbon tetrachloride, and liver injury and repair were assessed. After carbon tetrachloride, HIF-1α was activated in HSCs. Although liver injury was not different between the two strains of mice, during resolution of injury, clearance of necrotic cells was decreased in HIF-1α-GFAP Cre+ mice. In these mice, the persistence of necrotic cells stimulated a fibrotic response characterized by extensive collagen deposition. Hepatic accumulation of macrophages, which clear necrotic cells from the liver after carbon tetrachloride, was not affected by HIF-1α deletion in HSCs. Conversion of macrophages to M1-like, proinflammatory macrophages, which have increased phagocytic activity, however, was reduced in HIF-1α-GFAP Cre+ mice as indicated by a decrease in proinflammatory cytokines and a decrease in the percentage of Gr1(hi) macrophages. Collectively, these studies have identified a novel function for HSCs and HIF-1α in orchestrating the clearance of necrotic cells from the liver and demonstrated a key role for HSCs in modulating macrophage phenotype during acute liver injury.

PubMed ID: 24639359

MeSH Terms: Animals; Carbon Tetrachloride/pharmacology; Cell Proliferation; Chemical and Drug Induced Liver Injury/genetics; Chemical and Drug Induced Liver Injury/metabolism; Chemical and Drug Induced Liver Injury/pathology; Gene Deletion; Hepatic Stellate Cells/drug effects; Hepatic Stellate Cells/metabolism*; Hepatocytes/drug effects; Hepatocytes/metabolism; Hepatocytes/pathology; Hypoxia-Inducible Factor 1, alpha Subunit/genetics; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*; Liver Cirrhosis/genetics; Liver Cirrhosis/metabolism; Liver Cirrhosis/pathology; Macrophages/immunology*; Macrophages/metabolism*; Macrophages/pathology; Mice; Mice, Transgenic; Necrosis; Neutrophils/immunology; Neutrophils/metabolism; Neutrophils/pathology; Phenotype*; Urokinase-Type Plasminogen Activator/genetics; Urokinase-Type Plasminogen Activator/metabolism