Research ArticleINNATE IMMUNITY

The metabolic regulator mTORC1 controls terminal myeloid differentiation

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Science Immunology  26 May 2017:
Vol. 2, Issue 11, eaam6641
DOI: 10.1126/sciimmunol.aam6641

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Differentiating myeloid cells

Hematopoietic stem cells are a common progenitor of adaptive and innate immune cells. However, the precise factors that guide differentiation down these disparate pathways remain unclear in part because of difficulties working with small numbers of precursor cells. Lee et al. solve this problem for myeloid lineage cells by immortalizing murine myeloid progenitors with conditionally overexpressed Hoxb8 and labeling these cells with a Ccr2/Cx3cr1 dual reporter. They found through a small-molecule library screen and confirmatory in vivo validation that the mTORC1-S6K1-Myc pathway regulates myeloid differentiation. Disrupting this pathway in progenitors results in lack of monocytes and neutrophils. Hence, the mTORC1-S6K1-Myc pathway functions as a checkpoint in terminal myeloid differentiation.

Abstract

Monocytes are derived from hematopoietic stem cells through a series of intermediate progenitor stages, but the factors that regulate this process are incompletely defined. Using a Ccr2/Cx3cr1 dual-reporter system to model murine monocyte ontogeny, we conducted a small-molecule screen that identified an essential role of mechanistic target of rapamycin complex 1 (mTORC1) in the development of monocytes and other myeloid cells. Confirmatory studies using mice with inducible deletion of the mTORC1 component Raptor demonstrated absence of mature circulating monocytes, as well as disruption in neutrophil and dendritic cell development, reflecting arrest of terminal differentiation at the granulocyte-monocyte progenitor stage. Conversely, excess activation of mTORC1 through deletion of the mTORC1 inhibitor tuberous sclerosis complex 2 promoted spontaneous myeloid cell development and maturation. Inhibitor studies and stage-specific expression profiling identified failure to down-regulate the transcription factor Myc by the mTORC1 target ribosomal S6 kinase 1 (S6K1) as the mechanistic basis for disrupted myelopoiesis. Together, these findings define the mTORC1-S6K1-Myc pathway as a key checkpoint in terminal myeloid development.

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