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 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.
Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland.
Andrew L
AL
Croxford
Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland.
Margit
M
Lanzinger
Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland.
Felix J
FJ
Hartmann
Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland.
Bettina
B
Schreiner
Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland.
Florian
F
Mair
Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland.
Pawel
P
Pelczar
Institute for Molecular Medicine, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Björn E
BE
Clausen
Department of Immunology, Weizmann Institute of Science, 76100 Rehovot, Israel.
Steffen
S
Jung
Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland.
Melanie
M
Greter
Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland. Electronic address: becher@immunology.uzh.ch.
Burkhard
B
Becher
D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D053648:Cytokine Receptor Common beta Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D054390:Receptors, CCR2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics / Q000276:immunology
D000950:Antigens, Ly; C515335:Ccr2 protein, mouse; D053648:Cytokine Receptor Common beta Subunit; D053583:Interleukin-1beta; C494192:Ly-6C antigen, mouse; D054390:Receptors, CCR2; D050799:STAT5 Transcription Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor