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

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 condition...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Vol. 43; no. 3; p. 502
Main Authors: Croxford, Andrew L, Lanzinger, Margit, Hartmann, Felix J, Schreiner, Bettina, Mair, Florian, Pelczar, Pawel, Clausen, Björn E, Jung, Steffen, Greter, Melanie, Becher, Burkhard
Format: Journal Article
Language:English
Published: United States 15.09.2015
Subjects:
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
Signal Transduction - drug effects
Signal Transduction - genetics
Signal Transduction - immunology
STAT5 Transcription Factor - immunology
STAT5 Transcription Factor - metabolism
Transcriptome - drug effects
Transcriptome - genetics
Transcriptome - immunology
ISSN:1097-4180, 1097-4180
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Summary: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.
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ISSN:1097-4180
1097-4180
DOI:10.1016/j.immuni.2015.08.010