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

The cytokine transforming growth factor-beta (TGF-beta) regulates the development and homeostasis of several tissueresident macrophage populations, including microglia. TGF-beta 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-beta for colonization of the microglial niche and maintenance of CNS integrity is unknown. We found that abrogation of TGF-beta 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-beta is thus crucial for the functional integration of monocytes into the CNS microenvironment.