Transcriptomes of Tgfbr2 Knockout Microglia and Macrophages

The cytokine transforming growth factor-B (TGF-B) regulates development and homeostasis of several tissue-resident macrophage populations, including microglia. TGF-B is not critical for microglia survival, but is required for the maintenance of the microglia-specific homeostatic gene signature. 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). Whether monocytes require TGF-B for colonization of the microglial niche and maintenance of CNS integrity is unknown. We found that abrogation of TGF-B 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. The devastating motor disease that developed in TGF-BR2-deficient chimeras indicated that in the absence of TGF-B signaling the CNS environment licenses monocyte-derived macrophages for tissue damage. We therefore addressed how the gene expression signature of CNS macrophages was controlled by TGF-B signaling. We thus sorted TGF-BR2-deficient monocyte-derived macrophages from animals with ongoing motor disease and from their wildtype littermate counterparts. For comparison we sorted wild-type and TGF-BR2-deficient microglia and performed RNA sequencing for all four groups. Tgfbr2-deficient macrophages were characterized by high expression of genes encoding proteins involved in antigen presentation, inflammation and phagocytosis. TGF-B is thus crucial for the functional integration of monocytes into the CNS microenvironment. Transcriptome sequencing of WT and conditional-Tgfbr2 knockout microglia and CNS-repopulating monocyte-derived macrophages from C57BL/6 mouse in triplicates