title: The Heterogeneity of Ly6ChiMonocytes Controls Their Differentiation into iNOS+Macrophages or Monocyte-Derived Dendritic Cells.
abstract: Inflammation triggers the differentiation of Ly6Chimonocytes 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.1hisubset. 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.1lomonocytes 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.
authors.affiliation: 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.
authors.forename: Shinelle
authors.initials: S
authors.lastname: Menezes
authors.affiliation: 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.
authors.forename: Daisy
authors.initials: D
authors.lastname: Melandri
authors.affiliation: 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.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Anselmi
authors.affiliation: Pasteur Institute, 75724 Paris, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Perchet
authors.affiliation: The Rockefeller University, New York, NY 10065, USA.
authors.forename: Jakob
authors.initials: J
authors.lastname: Loschko
authors.affiliation: Geneva University, 1211 Geneva, Switzerland.
authors.forename: Juan
authors.initials: J
authors.lastname: Dubrot
authors.affiliation: 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.
authors.forename: Rajen
authors.initials: R
authors.lastname: Patel
authors.affiliation: Pitié-Salpêtrière Hospital, 75013 Paris, France.
authors.forename: Emmanuel L
authors.initials: EL
authors.lastname: Gautier
authors.affiliation: Geneva University, 1211 Geneva, Switzerland.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Hugues
authors.affiliation: Barts and the London School of Medicine, EC1M 6BQ London, UK.
authors.forename: M Paula
authors.initials: MP
authors.lastname: Longhi
authors.affiliation: University College London, WC1E 6BT London, UK.
authors.forename: Jake Y
authors.initials: JY
authors.lastname: Henry
authors.affiliation: University College London, WC1E 6BT London, UK.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Quezada
authors.affiliation: Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: Grégoire
authors.initials: G
authors.lastname: Lauvau
authors.affiliation: Institut Curie, 75248 Paris, France.
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Lennon-Duménil
authors.affiliation: 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.
authors.forename: Enrique
authors.initials: E
authors.lastname: Gutiérrez-Martínez
authors.affiliation: École Normale Supérieure, 75230 Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Bessis
authors.affiliation: Pasteur Institute, 75724 Paris, France.
authors.forename: Elisa
authors.initials: E
authors.lastname: Gomez-Perdiguero
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Christian E
authors.initials: CE
authors.lastname: Jacome-Galarza
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Garner
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Frederic
authors.initials: F
authors.lastname: Geissmann
authors.affiliation: Pasteur Institute, 75724 Paris, France.
authors.forename: Rachel
authors.initials: R
authors.lastname: Golub
authors.affiliation: The Rockefeller University, New York, NY 10065, USA.
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.affiliation: 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.
authors.forename: Pierre
authors.initials: P
authors.lastname: Guermonprez
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000950:Antigens, Ly / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005434:Flow Cytometry; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction
chemical_list: D000950:Antigens, Ly; C494192:Ly-6C antigen, mouse; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: GM-CSF; PU.1 transcription factor; macrophages; monocyte-derived dendritic cells; monocytes