title: Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation.
abstract: Macrophage activation/polarization to distinct functional states is critically supported by metabolic shifts. How polarizing signals coordinate metabolic and functional reprogramming, and the potential implications for control of macrophage activation, remains poorly understood. Here we show that IL-4 signaling co-opts the Akt-mTORC1 pathway to regulate Acly, a key enzyme in Ac-CoA synthesis, leading to increased histone acetylation and M2 gene induction. Only a subset of M2 genes is controlled in this way, including those regulating cellular proliferation and chemokine production. Moreover, metabolic signals impinge on the Akt-mTORC1 axis for such control of M2 activation. We propose that Akt-mTORC1 signaling calibrates metabolic state to energetically demanding aspects of M2 activation, which may define a new role for metabolism in supporting macrophage activation.
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Covarrubias
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States.
authors.forename: Halil Ibrahim
authors.identifier: http://orcid.org/0000-0002-0527-6124
authors.initials: HI
authors.lastname: Aksoylar
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States.
authors.forename: Jiujiu
authors.initials: J
authors.lastname: Yu
authors.affiliation: Center of Excellence in Environmental Toxicology, University of Pennsylvania, Philadelphia, United States.|A.J. Drexel Autism Institute, Drexel University, Philadelphia, United States.
authors.forename: Nathaniel W
authors.initials: NW
authors.lastname: Snyder
authors.affiliation: Center of Excellence in Environmental Toxicology, University of Pennsylvania, Philadelphia, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Worth
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, United States.
authors.forename: Shankar S
authors.initials: SS
authors.lastname: Iyer
authors.affiliation: Institute for Plant Physiology and Ecology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States.
authors.forename: Issam
authors.initials: I
authors.lastname: Ben-Sahra
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Byles
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Polynne-Stapornkul
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States.
authors.forename: Erika C
authors.initials: EC
authors.lastname: Espinosa
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, United States.
authors.forename: Dudley
authors.initials: D
authors.lastname: Lamming
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States.
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Manning
authors.affiliation: Institute for Plant Physiology and Ecology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yijing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center of Excellence in Environmental Toxicology, University of Pennsylvania, Philadelphia, United States.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Horng
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000378:metabolism*; D000107:Acetylation; D000818:Animals; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism* / Q000502:physiology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D018925:Chemokines; D006657:Histones; C508598:IL4 protein, human; D046912:Multiprotein Complexes; D015847:Interleukin-4; D001275:ATP Citrate (pro-S)-Lyase; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: acly; akt; cell biology; immunology; immunometabolism; mTORC1; macrophage activation; macrophage metabolism; mouse