The Cytokine GM-CSF Drives the Inflammatory Signature of CCR2+ Monocytes and Licenses Autoimmunity

Andrew L Croxford; Margit Lanzinger; Felix J Hartmann; Bettina Schreiner; Florian Mair; Pawel Pelczar; Björn E Clausen; Steffen Jung; Melanie Greter; Burkhard Becher

doi:10.1016/j.immuni.2015.08.010

The Cytokine GM-CSF Drives the Inflammatory Signature of CCR2+ Monocytes and Licenses Autoimmunity

Immunity. 2015 Sep 15;43(3):502-14. doi: 10.1016/j.immuni.2015.08.010. Epub 2015 Sep 1.

Affiliations

¹ Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland.
² Institute for Molecular Medicine, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
³ Department of Immunology, Weizmann Institute of Science, 76100 Rehovot, Israel.
⁴ Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland. Electronic address: becher@immunology.uzh.ch.

PMID: 26341401
DOI: 10.1016/j.immuni.2015.08.010

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has emerged as a crucial cytokine produced by auto-reactive T helper (Th) cells that initiate tissue inflammation. Multiple cell types can sense GM-CSF, but the identity of the pathogenic GM-CSF-responsive cells is unclear. By using conditional gene targeting, we systematically deleted the GM-CSF receptor (Csf2rb) in specific subpopulations throughout the myeloid lineages. Experimental autoimmune encephalomyelitis (EAE) progressed normally when either classical dendritic cells (cDCs) or neutrophils lacked GM-CSF responsiveness. The development of tissue-invading monocyte-derived dendritic cells (moDCs) was also unperturbed upon Csf2rb deletion. Instead, deletion of Csf2rb in CCR2(+)Ly6C(hi) monocytes phenocopied the EAE resistance seen in complete Csf2rb-deficient mice. High-dimensional analysis of tissue-infiltrating moDCs revealed that GM-CSF initiates a combination of inflammatory mechanisms. These results indicate that GM-CSF signaling controls a pathogenic expression signature in CCR2(+)Ly6C(hi) monocytes and their progeny, which was essential for tissue damage.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, Ly / genetics
Antigens, Ly / immunology
Antigens, Ly / metabolism
Autoimmunity / genetics
Autoimmunity / immunology*
Cytokine Receptor Common beta Subunit / genetics
Cytokine Receptor Common beta Subunit / immunology
Cytokine Receptor Common beta Subunit / metabolism
Dendritic Cells / drug effects
Dendritic Cells / immunology
Dendritic Cells / metabolism
Encephalomyelitis, Autoimmune, Experimental
Flow Cytometry
Granulocyte-Macrophage Colony-Stimulating Factor / immunology*
Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
Humans
Inflammation / genetics
Inflammation / immunology*
Inflammation / metabolism
Interleukin-1beta / genetics
Interleukin-1beta / immunology
Interleukin-1beta / metabolism
Mice, Knockout
Mice, Transgenic
Monocytes / drug effects
Monocytes / immunology*
Monocytes / metabolism
Myeloid Cells / drug effects
Myeloid Cells / immunology
Myeloid Cells / metabolism
Phosphorylation / drug effects
Phosphorylation / immunology
Receptors, CCR2 / genetics
Receptors, CCR2 / immunology*
Receptors, CCR2 / metabolism
Reverse Transcriptase Polymerase Chain Reaction
STAT5 Transcription Factor / immunology
STAT5 Transcription Factor / metabolism
Signal Transduction / drug effects
Signal Transduction / genetics
Signal Transduction / immunology*
Transcriptome / drug effects
Transcriptome / genetics
Transcriptome / immunology

Substances

Antigens, Ly
Ccr2 protein, mouse
Cytokine Receptor Common beta Subunit
Interleukin-1beta
Ly-6C antigen, mouse
Receptors, CCR2
STAT5 Transcription Factor
Granulocyte-Macrophage Colony-Stimulating Factor