Journal
IMMUNITY
Volume 43, Issue 3, Pages 502-514Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2015.08.010
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Funding
- Swiss national science foundation [PP00P3_144781, 310030_146130, 316030_150768]
- European Union, FP7 ITN_NeuroKine
- European Union FP7 project TargetBraIn [279017]
- Swiss Multiple Sclerosis Society
- University Priority Project Translational Cancer Research
- EMBO Long term Fellowship [ALTF 508-2011]
- Forschungskredit - University of Zurich
- Swiss National Science Foundation (SNF) [PP00P3_144781] Funding Source: Swiss National Science Foundation (SNF)
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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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