Forkhead Box M1 Transcription Factor Is Required for Macrophage Recruitment during Liver Repair

Acute liver injury results from exposure to toxins, pharmacological agents, or viral infections, contributing to significant morbidity and mortality worldwide.While hepatic inflammation is critical for liver repair, the transcriptional mechanisms required for the recruitment of inflammatory cells to the liver are not understood.Forkhead box M1 (Foxm1) transcription factor is a master regulator of hepatocyte proliferation, but its role in inflammatory cells remains unknown.In this study, we generated transgenic mice in which Foxm1 was deleted from myeloid-derived cells, including macrophages, monocytes, and neutrophils.Carbon tetrachloride liver injury was used to demonstrate that myeloid-specific Foxm1 deletion caused a delay in liver repair.Although Foxm1 deficiency did not influence neutrophil infiltration into injured livers, the total numbers of mature macrophages were dramatically reduced.Surprisingly, Foxm1 deficiency did not influence the proliferation of macrophages or their monocytic precursors but impaired monocyte recruitment during liver repair.Expression of L-selectin and the CCR2 chemokine receptor, both critical for monocyte recruitment to injured tissues, was decreased.Foxm1 induced transcriptional activity of the mouse CCR2 promoter in cotransfection experiments.Adoptive transfer of monocytes to Foxm1-deficient mice restored liver repair and rescued liver function.Foxm1 is critical for liver repair and is required for the recruitment of monocytes to the injured liver.Acute liver injury and underlying hepatic inflammation result from a variety of insults, including natural and industrial toxins, pharmacological agents, and viral infections, contributing to significant morbidity and mortality worldwide (6).In some patients, acute liver injury progresses to acute (fulminant) hepatic failure (FHF), a severe life-threatening disease characterized by impairment of liver function and hepatic encephalopathy (34).Before the emergence of liver transplantation, the survival rates for patients with FHF were as low as 15% (8).In recent years, 10% of annual liver transplantations are due to FHF (8).Acute liver injury can also trigger chronic inflammatory liver disease characterized by hepatic fibrosis and cirrhosis, leading to liver failure (7).Acute liver injury is characterized by necrosis of hepatocytes surrounding the central vein caused by local expression of a P450 enzyme forming toxic free-radical metabolites (32).Hepatic repair following acute liver injuries involves a proliferation of periportal hepatocytes and transient differentiation of stellate cells into fibrogenic myofibroblasts, which secrete collagen that is essential for reestablishment of normal liver architecture (7).During acute liver injury, recruitment of inflammatory cells such as macrophages, monocytes, and neutrophils to the site of injury and inflammation is an important event in removing necrotic tissue and normal liver repair (1, 7).The transcription factors required for the recruitment of inflammatory cells during liver repair are not understood.The Forkhead box (Fox) proteins are a large family of tran-