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

Publication date: 20 December 2016
Source:Immunity, Volume 45, Issue 6
Author(s): 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, Rachel Golub, Michel C. Nussenzweig, Pierre Guermonprez
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.

Graphical abstract

Teaser

Monocytes can differentiate into multiple progenies during inflammation. Here, Menezes et al. show that monocytes from naive mice are heterogeneous and contain distinct precursor subsets giving rise to iNOS⁺ inflammatory macrophages or GM-CSF-induced CD209a⁺ monocyte-derived dendritic cells.


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