Hepatic Stellate Cells Orchestrate Clearance of Necrotic Cells in a Hypoxia-Inducible Factor-1α-Dependent Manner by Modulating Macrophage Phenotype in Mice

Hypoxia-inducible factor-1a (HIF-1 alpha) is activated in hepatic stellate cells (HSCs) by hypoxia and regulates genes important for tissue repair. Whether HIF-1 alpha 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-1 alpha in HSCs by crossing HIF-1 alpha floxed mice with mice that express Cre recombinase under control of the glial fibrillary acidic protein (GFAP) promoter (i. e., HIF-1 alpha-GFAP Cre(+) mice). These mice and control mice (i. e., HIF-1 alpha-GFAP Cre-mice) were treated with a single dose of carbon tetrachloride, and liver injury and repair were assessed. After carbon tetrachloride, HIF-1a 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-1 alpha-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-1 alpha deletion in HSCs. Conversion of macrophages to M1-like, proinflammatory macrophages, which have increased phagocytic activity, however, was reduced in HIF-1 alpha-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-1 alpha 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.