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The Heterogeneity of Ly6C(hi) Monocytes Controls Their Differentiation into iNOS(+) Macrophages or Monocyte-Derived Dendritic Cells

Menezes, S; Melandri, D; Anselmi, G; Perchet, T; Loschko, J; Dubrot, J; Patel, R; ... Guermonprez, P; + view all (2016) The Heterogeneity of Ly6C(hi) Monocytes Controls Their Differentiation into iNOS(+) Macrophages or Monocyte-Derived Dendritic Cells. Immunity , 45 (6) pp. 1205-1218. 10.1016/j.immuni.2016.12.001. Green open access

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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.

Type: Article
Title: The Heterogeneity of Ly6C(hi) Monocytes Controls Their Differentiation into iNOS(+) Macrophages or Monocyte-Derived Dendritic Cells
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.immuni.2016.12.001
Publisher version: https://doi.org/10.1016/j.immuni.2016.12.001
Language: English
Additional information: Copyright © 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: monocytes; monocyte-derived dendritic cells; GM-CSF; macrophages; PU.1 transcription factor
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: https://discovery.ucl.ac.uk/id/eprint/1534904
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