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

Highlights

• GM-CSF controls diverse pathogenic capabilities of inflammatory myeloid cells

• GM-CSF induces an inflammatory response in CCR2⁺ monocytes required for tissue damage

• Neutrophils, cDCs, and microglia do not require GM-CSF signaling for EAE development

• GM-CSF signaling triggers an inflammatory signature in human monocytes

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.