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Hepatic stellate cells orchestrate clearance of necrotic cells from the liver by modulating macrophage phenotype (1115.6)
Author(s) -
Copple Bryan,
Rockwell Cheryl,
Luyendyk James
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1115.6
Subject(s) - hepatic stellate cell , glial fibrillary acidic protein , liver injury , macrophage , liver cytology , biology , ccl4 , tumor necrosis factor alpha , phenotype , inflammation , microbiology and biotechnology , chemistry , pathology , immunology , carbon tetrachloride , endocrinology , medicine , gene , in vitro , immunohistochemistry , biochemistry , organic chemistry , liver metabolism
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. Although liver injury, as measured by serum ALT activity, 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 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, pro‐inflammatory macrophages, which have increased phagocytic activity, however, was reduced in HIF‐1α‐GFAP Cre+ mice as indicated by a decrease in pro‐inflammatory cytokines, and a decrease in the percentage of Gr1hi 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.