| First Author | Mochizuki A | Year | 2014 |
| Journal | J Immunol | Volume | 192 |
| Issue | 8 | Pages | 3847-3857 |
| PubMed ID | 24639359 | Mgi Jnum | J:209999 |
| Mgi Id | MGI:5569218 | Doi | 10.4049/jimmunol.1303195 |
| Citation | Mochizuki A, et al. (2014) Hepatic stellate cells orchestrate clearance of necrotic cells in a hypoxia-inducible factor-1alpha-dependent manner by modulating macrophage phenotype in mice. J Immunol 192(8):3847-57 |
| abstractText | Hypoxia-inducible factor-1alpha (HIF-1alpha) is activated in hepatic stellate cells (HSCs) by hypoxia and regulates genes important for tissue repair. Whether HIF-1alpha 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-1alpha in HSCs by crossing HIF-1alpha floxed mice with mice that express Cre recombinase under control of the glial fibrillary acidic protein (GFAP) promoter (i.e., HIF-1alpha-GFAP Cre+ mice). These mice and control mice (i.e., HIF-1alpha-GFAP Cre- mice) were treated with a single dose of carbon tetrachloride, and liver injury and repair were assessed. After carbon tetrachloride, HIF-1alpha 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-1alpha-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-1alpha deletion in HSCs. Conversion of macrophages to M1-like, proinflammatory macrophages, which have increased phagocytic activity, however, was reduced in HIF-1alpha-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-1alpha 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. |
