Microglia-derived TGF-β1 ligand maintains microglia homeostasis via autocrine mechanism and is critical for normal cognitive function in adult mouse brain

While TGF-β signaling is essential for microglial function, the cellular source of TGF-β 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-β1 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-β1 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-β1 ligand we established an autocrine mechanism for TGF-β signaling. Importantly MG-Tgfb1 inducible KO mice show cognitive deficits, supporting that precise spatial regulation of TGF-β1 ligand derived from microglia is critical for the maintenance of brain homeostasis and normal cognitive function in the adult brain. enzymatically dissociated FACS microglia and astrocytes from Cx3cr1CreERT2 controls and Cx3cr1CreERT2-Tgfb1fl/fl