Fatal demyelinating disease is induced by monocyte-derived macrophages in the absence of TGF-β signaling

The cytokine transforming growth factor- β (TGF- β ) regulates the development and homeostasis of several tissue-resident macrophage populations, including microglia. TGF- β is not critical for microglia survival but is required for the maintenance of the microglia-specific homeostatic gene signature 1 , 2 . Under defined host conditions, circulating monocytes can compete for the microglial niche and give rise to long-lived monocyte-derived macrophages residing in the central nervous system (CNS) 3 – 5 . Whether monocytes require TGF- β for colonization of the microglial niche and maintenance of CNS integrity is unknown. We found that abrogation of TGF- β signaling in CX3CR1 + monocyte-derived macrophages led to rapid onset of a progressive and fatal demyelinating motor disease characterized by myelin-laden giant macrophages throughout the spinal cord. Tgfbr2- deficient macrophages were characterized by high expression of genes encoding proteins involved in antigen presentation, inflammation and phagocytosis. TGF- β is thus crucial for the functional integration of monocytes into the CNS microenvironment.