IRF8 inhibits C/EBPα activity to restrain mononuclear phagocyte progenitors from differentiating into neutrophils

Daisuke Kurotaki, Michio Yamamoto, Akira Nishiyama, Kazuhiro Uno, Tatsuma Ban, Motohide Ichino, Haruka Sasaki, Satoko Matsunaga, Masahiro Yoshinari, Akihide Ryo, Masatoshi Nakazawa, Keiko Ozato and Tomohiko Tamura ()
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Daisuke Kurotaki: Yokohama City University Graduate School of Medicine
Michio Yamamoto: Yokohama City University Graduate School of Medicine
Akira Nishiyama: Yokohama City University Graduate School of Medicine
Kazuhiro Uno: Yokohama City University Graduate School of Medicine
Tatsuma Ban: Yokohama City University Graduate School of Medicine
Motohide Ichino: Yokohama City University Graduate School of Medicine
Haruka Sasaki: Yokohama City University Graduate School of Medicine
Satoko Matsunaga: Yokohama City University Graduate School of Medicine
Masahiro Yoshinari: Yokohama City University Graduate School of Medicine
Akihide Ryo: Yokohama City University Graduate School of Medicine
Masatoshi Nakazawa: Yokohama City University Graduate School of Medicine
Keiko Ozato: Program in Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Tomohiko Tamura: Yokohama City University Graduate School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5978

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