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Nat Commun. 2014 Sep 19;5:4978. doi: 10.1038/ncomms5978.

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

Author information

1
Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
2
Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
3
Department of Experimental Animal Science, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
4
Program in Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.

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.

PMID:
25236377
DOI:
10.1038/ncomms5978
[Indexed for MEDLINE]

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