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

Research output: Contribution to journalArticle

Shinelle Menezes, Daisy Melandri, Giorgio Anselmi, Thibaut Perchet, Jakob Loschko, Juan Dubrot, Rajen Patel, Emmanuel L. Gautier, Stéphanie Hugues, M. Paula Longhi, Jake Y. Henry, Sergio A. Quezada, Grégoire Lauvau, Ana Maria Lennon-Duménil, Enrique Gutiérrez-Martínez, Alain Bessis, Elisa Gomez-Perdiguero, Christian E. Jacome-Galarza, Hannah Garner, Frederic Geissmann & 3 more Rachel Golub, Michel C. Nussenzweig, Pierre Guermonprez

Original languageEnglish
Pages (from-to)1205-1218
Number of pages14
JournalImmunity
Volume45
Issue number6
Early online date20 Dec 2016
DOIs
Accepted/In press24 Oct 2016
E-pub ahead of print20 Dec 2016
Published20 Dec 2016

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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+CD11cMHCII+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, Flt3CD11cMHCIIPU.1lo monocytes differentiated into FcγRIII+PD-L2CD209aiNOS+ 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+CD11cMHCII+ 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.

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