title: IRF8 inhibits C/EBPα activity to restrain mononuclear phagocyte progenitors from differentiating into neutrophils.
abstract: Myeloid progenitors lose their potential to generate neutrophils when they adopt the mononuclear phagocyte lineage. The mechanism underlying this lineage restriction remains unknown. We here report that the protein expression of IRF8, an essential transcription factor for the development of dendritic cells (DCs) and monocytes, sharply increases at the monocyte-DC progenitor (MDP) stage and remains high in common monocyte progenitors (cMoPs). Irf8(-/-) MDPs and cMoPs accumulate but fail to efficiently generate their downstream populations, instead giving rise to neutrophils in vivo. IRF8 physically interacts with the transcription factor C/EBPα and prevents its binding to chromatin in MDPs and cMoPs, blocking the ability of C/EBPα to stimulate transcription and neutrophil differentiation. A partial inhibition of C/EBP activity in Irf8(-/-) haematopoietic progenitors alleviates the neutrophil overproduction in vivo. Thus, IRF8 not only bestows monocyte and DC differentiation potential upon mononuclear phagocyte progenitors but also restrains these progenitors from differentiating into neutrophils.
authors.affiliation: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kurotaki
authors.affiliation: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.affiliation: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Uno
authors.affiliation: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Tatsuma
authors.initials: T
authors.lastname: Ban
authors.affiliation: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Motohide
authors.initials: M
authors.lastname: Ichino
authors.affiliation: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Matsunaga
authors.affiliation: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yoshinari
authors.affiliation: Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Ryo
authors.affiliation: Department of Experimental Animal Science, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Nakazawa
authors.affiliation: Program in Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
authors.affiliation: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000037:antagonists & inhibitors*; D002454:Cell Differentiation; D002843:Chromatin / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006412:Hematopoietic Stem Cells / Q000166:cytology; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology*; D010586:Phagocytes / Q000166:cytology*; D013234:Stem Cells / Q000166:cytology; D059467:Transcriptome; D000099185:Interferon Regulatory Factor-8
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D002843:Chromatin; D050835:Interferon Regulatory Factors; D000099185:Interferon Regulatory Factor-8