Microglia-derived TGF-ß1 ligand maintains microglia homeostasis via autocrine mechanism and is critical for normal cognitive function in adult mouse brain

While TGF-ß signaling is essential for microglial function, the cellular source of TGF-ß ligand and its spatial regulation remains unclear in adult CNS. Our data supports that microglia but not astrocytes or neurons are the primary producers of TGF-ß1 ligands needed for microglial homeostasis. Microglia-Tgfb1 KO leads to activation of microglia featuring a dyshomeostatic transcriptomic profile that resembles disease-associated microglia (DAMs), injury-associated microglia, and aged microglia, suggesting that microglial self-produced TGF-ß1 ligands are important in the adult CNS. Interestingly, astrocytes in the MG-tgfb1 iKO mice show a transcriptome profile that is closely aligned with A1-like astrocytes. Additionally, using sparse mosaic single cell microglia KO of TGF-ß1 ligand we established an autocrine mechanism for TGF-ß signaling. Importantly MG-Tgfb1 inducible KO mice show cognitive deficits, supporting that precise spatial regulation of TGF-ß1 ligand derived from microglia is critical for the maintenance of brain homeostasis and normal cognitive function in the adult brain. Overall design: enzymatically dissociated FACS microglia and astrocytes from Cx3cr1CreERT2 controls and Cx3cr1CreERT2-Tgfb1fl/fl