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.
Ren
Xiaomeng
X
Department of Pediatrics, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Ave., Cincinnati, OH 45229, USA.
Zhang
Yufang
Y
Snyder
Jonathan
J
Cross
Emily R
ER
Shah
Tushar A
TA
Kalin
Tanya V
TV
Kalinichenko
Vladimir V
VV
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D002251:Carbon Tetrachloride / Q000494:pharmacology; D049109:Cell Proliferation; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019041:L-Selectin / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000293:injuries* / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*
D015703:Antigens, CD; C515335:Ccr2 protein, mouse; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D054390:Receptors, CCR2; D019041:L-Selectin; D002251:Carbon Tetrachloride