title: Hepatic stellate cells orchestrate clearance of necrotic cells in a hypoxia-inducible factor-1α-dependent manner by modulating macrophage phenotype in mice.
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.
authors.affiliation: Department of Pharmacology and Toxicology Michigan State University, East Lansing, MI 48824.
authors.forename: Akie
authors.initials: A
authors.lastname: Mochizuki
authors.affiliation: Department of Pharmacology and Toxicology Michigan State University, East Lansing, MI 48824.
authors.forename: Aaron
authors.initials: A
authors.lastname: Pace
authors.affiliation: Department of Pharmacology and Toxicology Michigan State University, East Lansing, MI 48824.
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Rockwell
authors.affiliation: Department of Pharmacology and Toxicology Michigan State University, East Lansing, MI 48824.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Roth
authors.affiliation: Department of Pharmacology and Toxicology Michigan State University, East Lansing, MI 48824.
authors.forename: Aaron
authors.initials: A
authors.lastname: Chow
authors.affiliation: Department of Pharmacology and Toxicology Michigan State University, East Lansing, MI 48824.
authors.forename: Kate M
authors.initials: KM
authors.lastname: O'Brien
authors.affiliation: Department of Pharmacology and Toxicology Michigan State University, East Lansing, MI 48824.
authors.forename: Ryan
authors.initials: R
authors.lastname: Albee
authors.affiliation: Department of Pharmacology and Toxicology Michigan State University, East Lansing, MI 48824.
authors.forename: Kara
authors.initials: K
authors.lastname: Kelly
authors.affiliation: Department of Pathobiology and Diagnostic Investigation Michigan State University, East Lansing, MI 48824.
authors.forename: Keara
authors.initials: K
authors.lastname: Towery
authors.affiliation: Department of Pathobiology and Diagnostic Investigation Michigan State University, East Lansing, MI 48824.
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
authors.affiliation: Department of Pharmacology and Toxicology Michigan State University, East Lansing, MI 48824.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Copple
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000494:pharmacology; D049109:Cell Proliferation; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009336:Necrosis; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D002251:Carbon Tetrachloride; D014568:Urokinase-Type Plasminogen Activator