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

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

doi:10.1016/j.immuni.2016.12.001

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

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 GeissmannRachel Golub, Michel C. Nussenzweig, Pierre Guermonprez^*

^*Corresponding author for this work

Peter Gorer Department of Immunobiology

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	1205-1218
Number of pages	14
Journal	Immunity
Volume	45
Issue number	6
Early online date	20 Dec 2016
DOIs	https://doi.org/10.1016/j.immuni.2016.12.001
Publication status	Published - 20 Dec 2016

Keywords

GM-CSF
macrophages
monocyte-derived dendritic cells
monocytes
PU.1 transcription factor

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The heterogeneity of Ly6Chi_MENEZES_Accepted24October2016Firstonline20December2016_GOLD VoRFinal published version, 4.06 MBLicence: CC BY

Cite this

Menezes, S., Melandri, D., Anselmi, G., Perchet, T., Loschko, J., Dubrot, J., Patel, R., Gautier, E. L., Hugues, S., Longhi, M. P., Henry, J. Y., Quezada, S. A., Lauvau, G., Lennon-Duménil, A. M., Gutiérrez-Martínez, E., Bessis, A., Gomez-Perdiguero, E., Jacome-Galarza, C. E., Garner, H., ... Guermonprez, P. (2016). The Heterogeneity of Ly6C^hi Monocytes Controls Their Differentiation into iNOS⁺ Macrophages or Monocyte-Derived Dendritic Cells. Immunity, 45(6), 1205-1218. https://doi.org/10.1016/j.immuni.2016.12.001

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

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.",

keywords = "GM-CSF, macrophages, monocyte-derived dendritic cells, monocytes, PU.1 transcription factor",

author = "Shinelle Menezes and Daisy Melandri and Giorgio Anselmi and Thibaut Perchet and Jakob Loschko and Juan Dubrot and Rajen Patel and Gautier, {Emmanuel L.} and St{\'e}phanie Hugues and Longhi, {M. Paula} and Henry, {Jake Y.} and Quezada, {Sergio A.} and Gr{\'e}goire Lauvau and Lennon-Dum{\'e}nil, {Ana Maria} and Enrique Guti{\'e}rrez-Mart{\'i}nez and Alain Bessis and Elisa Gomez-Perdiguero and Jacome-Galarza, {Christian E.} and Hannah Garner and Frederic Geissmann and Rachel Golub and Nussenzweig, {Michel C.} and Pierre Guermonprez",

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Menezes, S , Melandri, D , Anselmi, G, Perchet, T, Loschko, J, Dubrot, J, Patel, R, Gautier, EL, Hugues, S, Longhi, MP, Henry, JY, Quezada, SA, Lauvau, G, Lennon-Duménil, AM, Gutiérrez-Martínez, E, Bessis, A, Gomez-Perdiguero, E, Jacome-Galarza, CE, Garner, H, Geissmann, F, Golub, R, Nussenzweig, MC & Guermonprez, P 2016, 'The Heterogeneity of Ly6C^hi Monocytes Controls Their Differentiation into iNOS⁺ Macrophages or Monocyte-Derived Dendritic Cells', Immunity, vol. 45, no. 6, pp. 1205-1218. https://doi.org/10.1016/j.immuni.2016.12.001

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AU - Menezes, Shinelle

AU - Melandri, Daisy

AU - Anselmi, Giorgio

AU - Perchet, Thibaut

AU - Loschko, Jakob

AU - Dubrot, Juan

AU - Patel, Rajen

AU - Gautier, Emmanuel L.

AU - Hugues, Stéphanie

AU - Longhi, M. Paula

AU - Henry, Jake Y.

AU - Quezada, Sergio A.

AU - Lauvau, Grégoire

AU - Lennon-Duménil, Ana Maria

AU - Gutiérrez-Martínez, Enrique

AU - Bessis, Alain

AU - Gomez-Perdiguero, Elisa

AU - Jacome-Galarza, Christian E.

AU - Garner, Hannah

AU - Geissmann, Frederic

AU - Golub, Rachel

AU - Nussenzweig, Michel C.

AU - Guermonprez, Pierre

PY - 2016/12/20

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N2 - 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.

AB - 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.

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