PMID- 26811453 OWN - NLM STAT- MEDLINE DCOM- 20160704 LR - 20200227 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 113 IP - 6 DP - 2016 Feb 9 TI - Proinflammatory signal suppresses proliferation and shifts macrophage metabolism from Myc-dependent to HIF1alpha-dependent. PG - 1564-9 LID - 10.1073/pnas.1518000113 [doi] AB - 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 (HIF1alpha)-dependent transcriptional program that is responsible for heightened glycolysis. The acute deletion of Myc or HIF1alpha 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 HIF1alpha suppressed LPS-induced inflammation in vivo. Our studies indicate that a switch from a Myc-dependent to a HIF1alpha-dependent transcriptional program may regulate the robust bioenergetic support for an inflammatory response, while sparing Myc-dependent proliferation. FAU - Liu, Lingling AU - Liu L AD - 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; FAU - Lu, Yun AU - Lu Y AD - 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; FAU - Martinez, Jennifer AU - Martinez J AD - Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709; FAU - Bi, Yujing AU - Bi Y AD - State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 100101 Beijing, China; FAU - Lian, Gaojian AU - Lian G AD - 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; FAU - Wang, Tingting AU - Wang T AD - 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; FAU - Milasta, Sandra AU - Milasta S AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105. FAU - Wang, Jian AU - Wang J AD - 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; FAU - Yang, Mao AU - Yang M AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105. FAU - Liu, Guangwei AU - Liu G AD - 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. FAU - Green, Douglas R AU - Green DR AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105 ruoning.wang@nationwidechildrens.org liugw@fudan.edu.cn douglas.green@stjude.org. FAU - Wang, Ruoning AU - Wang R AD - 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. LA - eng GR - R21 AI117547/AI/NIAID NIH HHS/United States GR - P30 CA021765/CA/NCI NIH HHS/United States GR - P30 CA016058/CA/NCI NIH HHS/United States GR - R21AI117547/AI/NIAID NIH HHS/United States GR - R01 AI114581/AI/NIAID NIH HHS/United States GR - 1R01AI114581/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160125 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Lipopolysaccharides) RN - 0 (Mitogens) RN - 0 (Proto-Oncogene Proteins c-myc) RN - 0 (RNA, Messenger) RN - 81627-83-0 (Macrophage Colony-Stimulating Factor) RN - 82115-62-6 (Interferon-gamma) SB - IM MH - Animals MH - Cell Cycle/drug effects MH - Cell Polarity/drug effects MH - Cell Proliferation/drug effects MH - Disease Models, Animal MH - Gene Deletion MH - Glycolysis/drug effects MH - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism MH - Inflammation/*metabolism/*pathology MH - Interferon-gamma/pharmacology MH - Lipopolysaccharides/pharmacology MH - Macrophage Colony-Stimulating Factor/pharmacology MH - Macrophages/drug effects/*metabolism/*pathology MH - Metabolic Networks and Pathways/drug effects/genetics MH - Mice, Inbred C57BL MH - Mitogens/pharmacology MH - Proto-Oncogene Proteins c-myc/*metabolism MH - RNA, Messenger/genetics/metabolism MH - Sepsis/metabolism/pathology MH - *Signal Transduction/drug effects MH - Transcriptome/drug effects/genetics PMC - PMC4760828 OTO - NOTNLM OT - HIF1alpha OT - Myc OT - cell cycle OT - macrophage OT - metabolism COIS- The authors declare no conflict of interest. EDAT- 2016/01/27 06:00 MHDA- 2016/07/05 06:00 PMCR- 2016/01/25 CRDT- 2016/01/27 06:00 PHST- 2016/01/27 06:00 [entrez] PHST- 2016/01/27 06:00 [pubmed] PHST- 2016/07/05 06:00 [medline] PHST- 2016/01/25 00:00 [pmc-release] AID - 1518000113 [pii] AID - 201518000 [pii] AID - 10.1073/pnas.1518000113 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2016 Feb 9;113(6):1564-9. doi: 10.1073/pnas.1518000113. Epub 2016 Jan 25.