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

Shinelle Menezes 1, 2, 3 Daisy Melandri 1, 2, 3 Giorgio Anselmi 3 Thibaut Perchet 4 Jakob Loschko 5 Juan Dubrot 6 Rajen Patel 1, 2, 3 Emmanuel L. Gautier 7 Stéphanie Hugues 6 M. Paula Longhi 8 Jake Y. Henry 9 Sergio A. Quezada 9 Grégoire Lauvau 10 Ana-Maria Lennon-Duménil 11 Enrique Gutiérrez-Martínez 1, 2, 3 Alain Bessis 12 Elisa Gomez-Perdiguero 4 Christian E. Jacome-Galarza 13 Hannah Garner 13 Frederic Geissmann 13 Rachel Golub 4 Michel C. Nussenzweig 5 Pierre Guermonprez 1, 2, 3, *
* Corresponding author
1 Centre for Cellular and Molecular Biology of Inflammation
2 Peter Gorer Department of Immunobiology
3 laboratory of phagocyte immunobiology
4 Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4) - Lymphopoïèse
5 Rockefeller University [New York]
6 University of Geneva [Switzerland]
7 CHU Pitié-Salpêtrière [AP-HP]
8 Barts and the London Medical School
9 UCL - University College of London [London]
10 Albert Einstein College of Medicine [New York]
11 Institut Curie [Paris]
12 ENS Paris - École normale supérieure - Paris
13 Memorial Sloane Kettering Cancer Center [New York]
Abstract : Inflammation triggers the differentiation of Ly6C(hi) 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.1(hi) 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.1(lo) 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 : monocyte-derived dendritic cells monocytes GM-CSF PU.1 transcription factor macrophages
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https://hal-pasteur.archives-ouvertes.fr/pasteur-01439253
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Submitted on : Wednesday, January 18, 2017 - 2:12:43 PM
Last modification on : Thursday, July 1, 2021 - 5:32:45 PM

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Shinelle Menezes, Daisy Melandri, Giorgio Anselmi, Thibaut Perchet, Jakob Loschko, et al.. The Heterogeneity of Ly6Chi Monocytes Controls Their Differentiation into iNOS+ Macrophages or Monocyte-Derived Dendritic Cells. Immunity, Elsevier, 2016, 45 (6), pp.1205 - 1218. ⟨10.1016/j.immuni.2016.12.001⟩. ⟨pasteur-01439253⟩

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