title: Proinflammatory signal suppresses proliferation and shifts macrophage metabolism from Myc-dependent to HIF1α-dependent.
abstract: As a phenotypically plastic cellular population, macrophages change their physiology in response to environmental signals. Emerging evidence suggests that macrophages are capable of tightly coordinating their metabolic programs to adjust their immunological and bioenergetic functional properties, as needed. Upon mitogenic stimulation, quiescent macrophages enter the cell cycle, increasing their bioenergetic and biosynthetic activity to meet the demands of cell growth. Proinflammatory stimulation, however, suppresses cell proliferation, while maintaining a heightened metabolic activity imposed by the production of bactericidal factors. Here, we report that the mitogenic stimulus, colony-stimulating factor 1 (CSF-1), engages a myelocytomatosis viral oncogen (Myc)-dependent transcriptional program that is responsible for cell cycle entry and the up-regulation of glucose and glutamine catabolism in bone marrow-derived macrophages (BMDMs). However, the proinflammatory stimulus, lipopolysaccharide (LPS), suppresses Myc expression and cell proliferation and engages a hypoxia-inducible factor alpha (HIF1α)-dependent transcriptional program that is responsible for heightened glycolysis. The acute deletion of Myc or HIF1α selectively impaired the CSF-1- or LPS-driven metabolic activities in BMDM, respectively. Finally, inhibition of glycolysis by 2-deoxyglucose (2-DG) or genetic deletion of HIF1α suppressed LPS-induced inflammation in vivo. Our studies indicate that a switch from a Myc-dependent to a HIF1α-dependent transcriptional program may regulate the robust bioenergetic support for an inflammatory response, while sparing Myc-dependent proliferation.
authors.affiliation: Center for Childhood Cancer & Blood Diseases, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, OH 43205; Hematology/Oncology & Blood and Marrow Transplant, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, OH 43205;
authors.forename: Lingling
authors.initials: L
authors.lastname: Liu
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, 200433 Shanghai, China; Department of Immunology, School of Basic Medical Sciences, Fudan University, 200433 Shanghai, China; Biotherapy Research Center, Institute of Immunobiology, Fudan University, 200433 Shanghai, China;
authors.forename: Yun
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Martinez
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 100101 Beijing, China;
authors.forename: Yujing
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Center for Childhood Cancer & Blood Diseases, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, OH 43205; Hematology/Oncology & Blood and Marrow Transplant, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, OH 43205; Medical Research Center, University of South China, 421101 Hengyang, Hunan Province, China;
authors.forename: Gaojian
authors.initials: G
authors.lastname: Lian
authors.affiliation: Center for Childhood Cancer & Blood Diseases, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, OH 43205; Hematology/Oncology & Blood and Marrow Transplant, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, OH 43205;
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Sandra
authors.initials: S
authors.lastname: Milasta
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, 200433 Shanghai, China; Department of Immunology, School of Basic Medical Sciences, Fudan University, 200433 Shanghai, China; Biotherapy Research Center, Institute of Immunobiology, Fudan University, 200433 Shanghai, China;
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Mao
authors.initials: M
authors.lastname: Yang
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, 200433 Shanghai, China; Department of Immunology, School of Basic Medical Sciences, Fudan University, 200433 Shanghai, China; Biotherapy Research Center, Institute of Immunobiology, Fudan University, 200433 Shanghai, China; ruoning.wang@nationwidechildrens.org liugw@fudan.edu.cn douglas.green@stjude.org.
authors.forename: Guangwei
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105 ruoning.wang@nationwidechildrens.org liugw@fudan.edu.cn douglas.green@stjude.org.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.affiliation: Center for Childhood Cancer & Blood Diseases, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, OH 43205; Hematology/Oncology & Blood and Marrow Transplant, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, OH 43205; ruoning.wang@nationwidechildrens.org liugw@fudan.edu.cn douglas.green@stjude.org.
authors.forename: Ruoning
authors.initials: R
authors.lastname: Wang
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D017353:Gene Deletion; D006019:Glycolysis / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics; D008810:Mice, Inbred C57BL; D008934:Mitogens / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008070:Lipopolysaccharides; D008934:Mitogens; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma
keywords: HIF1α; Myc; cell cycle; macrophage; metabolism
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