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Immunity. 2016 Dec 20;45(6):1205-1218. doi: 10.1016/j.immuni.2016.12.001.

The Heterogeneity of Ly6Chi Monocytes Controls Their Differentiation into iNOS+ Macrophages or Monocyte-Derived Dendritic Cells.

Author information

1
Laboratory of Phagocyte Immunobiology, King's College London, SE1 1UL London, UK; Centre for Inflammation Biology and Cancer Immunology, King's College London, SE1 1UL London, UK; Peter Gorer Department of Immunobiology, King's College London, SE1 1UL London, UK.
2
Pasteur Institute, 75724 Paris, France.
3
The Rockefeller University, New York, NY 10065, USA.
4
Geneva University, 1211 Geneva, Switzerland.
5
Pitié-Salpêtrière Hospital, 75013 Paris, France.
6
Barts and the London School of Medicine, EC1M 6BQ London, UK.
7
University College London, WC1E 6BT London, UK.
8
Albert Einstein College of Medicine, New York, NY 10461, USA.
9
Institut Curie, 75248 Paris, France.
10
École Normale Supérieure, 75230 Paris, France.
11
Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
12
Laboratory of Phagocyte Immunobiology, King's College London, SE1 1UL London, UK; Centre for Inflammation Biology and Cancer Immunology, King's College London, SE1 1UL London, UK; Peter Gorer Department of Immunobiology, King's College London, SE1 1UL London, UK. Electronic address: pierre.guermonprez@kcl.ac.uk.

Abstract

Inflammation triggers the differentiation of Ly6Chi monocytes into microbicidal macrophages or monocyte-derived dendritic cells (moDCs). Yet, it is unclear whether environmental inflammatory cues control the polarization of monocytes toward each of these fates or whether specialized monocyte progenitor subsets exist before inflammation. Here, we have shown that naive monocytes are phenotypically heterogeneous and contain an NR4A1- and Flt3L-independent, CCR2-dependent, Flt3+CD11c-MHCII+PU.1hi subset. This subset acted as a precursor for FcγRIII+PD-L2+CD209a+, GM-CSF-dependent moDCs but was distal from the DC lineage, as shown by fate-mapping experiments using Zbtb46. By contrast, Flt3-CD11c-MHCII-PU.1lo monocytes differentiated into FcγRIII+PD-L2-CD209a-iNOS+ macrophages upon microbial stimulation. Importantly, Sfpi1 haploinsufficiency genetically distinguished the precursor activities of monocytes toward moDCs or microbicidal macrophages. Indeed, Sfpi1+/- mice had reduced Flt3+CD11c-MHCII+ monocytes and GM-CSF-dependent FcγRIII+PD-L2+CD209a+ moDCs but generated iNOS+ macrophages more efficiently. Therefore, intercellular disparities of PU.1 expression within naive monocytes segregate progenitor activity for inflammatory iNOS+ macrophages or moDCs.

KEYWORDS:

GM-CSF; PU.1 transcription factor; macrophages; monocyte-derived dendritic cells; monocytes

PMID:
28002729
PMCID:
PMC5196026
DOI:
10.1016/j.immuni.2016.12.001
[Indexed for MEDLINE]
Free PMC Article

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