Hypoxia-Inducible Factor Activation in Myeloid Cells Contributes to the Development of Liver Fibrosis in Cholestatic Mice

Macrophages play an integral role in the development of liver fibrosis by releasing mediators, such as platelet-derived growth factor-B (PDGF-B) and transforming growth factor-beta 1, which stimulate hepatic stellate cell proliferation, chemotaxis, and collagen production. However, the mechanism by which chronic liver injury stimulates macrophages to release these mediators is not completely understood. We tested the hypothesis that chronic liver injury activates hypoxia-inducible factor (HIF) transcription factors in macrophages that regulate the production of mediators that promote fibrosis. To test this hypothesis, Cre/lox technology was used to generate myeloid cell-specific HIF-1 alpha or HIF-1 beta knockout mice. When these mice were subjected to bile duct ligation (BDL), levels of alpha-smooth muscle actin and type I collagen in the liver were reduced compared with those of mice with normal levels of HIFs. The deficiency of HIFs in macrophages did not affect liver injury or inflammation after BDL but reduced PDGF-B mRNA and protein, suggesting that HIF activation in macrophages may promote fibrosis by regulating the production of PDGF-B. Consistent with a role for HIFs in liver fibrosis in cholestatic liver disease, nuclear HIF-1 alpha protein was present in macrophages, hepatocytes, and fibroblasts in the livers from patients with primary biliary cirrhosis and primary sclerosing cholangitis. These studies demonstrate that HIFs are important regulators of profibrotic mediator production by macrophages during the development of liver fibrosis and suggest that HIFs may be a novel therapeutic target for the treatment of chronic liver disease in patients.