title: Polarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals.
abstract: Macrophages play crucial roles in host defence and tissue homoeostasis, processes in which both environmental stimuli and intracellularly generated metabolites influence activation of macrophages. Activated macrophages are classified into M1 and M2 macrophages. It remains unclear how intracellular nutrition sufficiency, especially for amino acid, influences on macrophage activation. Here we show that a lysosomal adaptor protein Lamtor1, which forms an amino-acid sensing complex with lysosomal vacuolar-type H+-ATPase (v-ATPase), and is the scaffold for amino acid-activated mTORC1 (mechanistic target of rapamycin complex 1), is critically required for M2 polarization. Lamtor1 deficiency, amino-acid starvation, or inhibition of v-ATPase and mTOR result in defective M2 polarization and enhanced M1 polarization. Furthermore, we identified liver X receptor (LXR) as the downstream target of Lamtor1 and mTORC1. Production of 25-hydroxycholesterol is dependent on Lamtor1 and mTORC1. Our findings demonstrate that Lamtor1 plays an essential role in M2 polarization, coupling immunity and metabolism.
authors.affiliation: Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Yamadaoka 2-2, Osaka 565-0871 Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Gobancho 7, Tokyo 102-0076, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Yamadaoka 3-1, Osaka 565-0871, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Nada
authors.affiliation: Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Yamadaoka 2-2, Osaka 565-0871 Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Takegahara
authors.affiliation: Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Yamadaoka 2-2, Osaka 565-0871 Japan.|Department of Neurology, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Osaka 565-0871, Japan.
authors.forename: Tatsusada
authors.initials: T
authors.lastname: Okuno
authors.affiliation: Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Yamadaoka 2-2, Osaka 565-0871 Japan.|The Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Gobancho 7, Tokyo 102-0076, Japan.|Department of Pathology, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Osaka 565-0871, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nojima
authors.affiliation: Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Yamadaoka 2-2, Osaka 565-0871 Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Gobancho 7, Tokyo 102-0076, Japan.
authors.forename: Sujin
authors.initials: S
authors.lastname: Kang
authors.affiliation: Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Yamadaoka 2-2, Osaka 565-0871 Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Gobancho 7, Tokyo 102-0076, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ito
authors.affiliation: Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Yamadaoka 2-2, Osaka 565-0871 Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Gobancho 7, Tokyo 102-0076, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Morimoto
authors.affiliation: Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Yamadaoka 2-2, Osaka 565-0871 Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Gobancho 7, Tokyo 102-0076, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hosokawa
authors.affiliation: Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Yamadaoka 2-2, Osaka 565-0871 Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Gobancho 7, Tokyo 102-0076, Japan.
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Hayama
authors.affiliation: Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Yamadaoka 2-2, Osaka 565-0871 Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Osaka 565-0871, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Mitsui
authors.affiliation: Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Yamadaoka 2-2, Osaka 565-0871 Japan.
authors.forename: Natsuki
authors.initials: N
authors.lastname: Sakurai
authors.affiliation: Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Yamadaoka 2-2, Osaka 565-0871 Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Gobancho 7, Tokyo 102-0076, Japan.
authors.forename: Hana
authors.initials: H
authors.lastname: Sarashina-Kida
authors.affiliation: Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Yamadaoka 2-2, Osaka 565-0871 Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Gobancho 7, Tokyo 102-0076, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nishide
authors.affiliation: Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Yamadaoka 2-2, Osaka 565-0871 Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Gobancho 7, Tokyo 102-0076, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Yamadaoka 2-2, Osaka 565-0871 Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Gobancho 7, Tokyo 102-0076, Japan.
authors.forename: Hyota
authors.initials: H
authors.lastname: Takamatsu
authors.affiliation: DNA-chip Development Center for Infectious Diseases, Research Institute for Microbial Diseases, Yamadaoka 3-1, Osaka 565-0871, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Okuzaki
authors.affiliation: Global Application Development Center, Analytical and Measuring Instruments Division, Shimadzu Corporation, Kyoto 604-8511, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Yamadaoka 3-1, Osaka 565-0871, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Okada
authors.affiliation: Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Yamadaoka 2-2, Osaka 565-0871 Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Osaka 565-0871, Japan.|The Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Gobancho 7, Tokyo 102-0076, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000276:immunology; D000596:Amino Acids / Q000172:deficiency / Q000276:immunology*; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation; D000071518:Liver X Receptors / Q000235:genetics / Q000276:immunology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009287:Naphthyridines / Q000494:pharmacology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D016207:Cytokines; D000071518:Liver X Receptors; D018942:Macrolides; D009287:Naphthyridines; C571152:late endosome-lysosome membrane adaptor p18, mouse; C036978:concanamycin A; C040929:bafilomycin A1; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D025262:Vacuolar Proton-Translocating ATPases; D020123:Sirolimus