title: Identification of an atypical monocyte and committed progenitor involved in fibrosis.
abstract: Monocytes and macrophages comprise a variety of subsets with diverse functions. It is thought that these cells play a crucial role in homeostasis of peripheral organs, key immunological processes and development of various diseases. Among these diseases, fibrosis is a life-threatening disease of unknown aetiology. Its pathogenesis is poorly understood, and there are few effective therapies. The development of fibrosis is associated with activation of monocytes and macrophages. However, the specific subtypes of monocytes and macrophages that are involved in fibrosis have not yet been identified. Here we show that Ceacam1+Msr1+Ly6C-F4/80-Mac1+monocytes, which we term segregated-nucleus-containing atypical monocytes (SatM), share granulocyte characteristics, are regulated by CCAAT/enhancer binding protein β (C/EBPβ), and are critical for fibrosis. Cebpb deficiency results in a complete lack of SatM. Furthermore, the development of bleomycin-induced fibrosis, but not inflammation, was prevented in chimaeric mice with Cebpb-/-haematopoietic cells. Adoptive transfer of SatM into Cebpb-/-mice resulted in fibrosis. Notably, SatM are derived from Ly6C-FcεRI+granulocyte/macrophage progenitors, and a newly identified SatM progenitor downstream of Ly6C-FcεRI+granulocyte/macrophage progenitors, but not from macrophage/dendritic-cell progenitors. Our results show that SatM are critical for fibrosis and that C/EBPβ licenses differentiation of SatM from their committed progenitor.
authors.affiliation: Laboratory of Host Defense, World Premier Institute Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan.|Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, Osaka, 565-0871, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Satoh
authors.affiliation: Laboratory of Host Defense, World Premier Institute Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan.|Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, Osaka, 565-0871, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: Laboratory of Biofunctional Imaging, World Premier Institute Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Sugihara
authors.affiliation: Research Center for Ultra-high Voltage Electron Microscopy, Osaka University, Osaka, 567-0047, Japan.
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Kuwahara
authors.affiliation: Discovery Research Department, Research Division, Chugai Pharmaceutical Co., Ltd., Kanagawa, 247-8530, Japan.
authors.forename: Motooki
authors.initials: M
authors.lastname: Ashihara
authors.affiliation: Laboratory of Host Defense, World Premier Institute Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan.|Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, Osaka, 565-0871, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Yamane
authors.affiliation: Discovery Research Department, Research Division, Chugai Pharmaceutical Co., Ltd., Kanagawa, 247-8530, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Minowa
authors.affiliation: Laboratory of Host Defense, World Premier Institute Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan.|Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, Osaka, 565-0871, Japan.
authors.forename: Kiyoharu
authors.initials: K
authors.lastname: Fukushima
authors.affiliation: Laboratory of Host Defense, World Premier Institute Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan.|Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, Osaka, 565-0871, Japan.|Discovery Research Department, Research Division, Chugai Pharmaceutical Co., Ltd., Kanagawa, 247-8530, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Ebina
authors.affiliation: Laboratory of Biofunctional Imaging, World Premier Institute Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan.
authors.forename: Yoshichika
authors.initials: Y
authors.lastname: Yoshioka
authors.affiliation: Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, 100-0004, Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
authors.affiliation: Laboratory of Host Defense, World Premier Institute Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan.|Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, Osaka, 565-0871, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001761:Bleomycin / Q000633:toxicity; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology; D004195:Disease Models, Animal; D055014:Granulocyte-Macrophage Progenitor Cells / Q000166:cytology* / Q000378:metabolism; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism; D007249:Inflammation; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy / Q000639:trends; D009000:Monocytes / Q000145:classification* / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D017455:Receptors, IgE / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000950:Antigens, Ly; D015415:Biomarkers; D022782:CCAAT-Enhancer-Binding Protein-beta; C069847:CD66 antigens; C545013:Cebpb protein, mouse; D015815:Cell Adhesion Molecules; C494192:Ly-6C antigen, mouse; C495140:Msr1 protein, mouse; D017455:Receptors, IgE; D051117:Scavenger Receptors, Class A; D001761:Bleomycin