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

Abstract

While TGF-{beta} signaling is essential for microglial function, the cellular source of TGF-{beta} ligand and its spatial regulation remains unclear in the adult CNS. Our data support that microglia, not astrocytes or neurons, are the primary producers of TGF-{beta}1 ligands needed for microglial homeostasis. Microglia (MG)-Tgfb1 inducible knockout (iKO) leads to the 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-{beta}1 ligands are important in the adult CNS. Interestingly, astrocytes in MG-Tgfb1 iKO mice show a transcriptome profile that closely aligns with A1-like astrocytes. Additionally, using sparse mosaic single-cell microglia iKO of TGF-{beta}1 ligand, we established an autocrine mechanism for TGF-{beta} signaling. Importantly MG-Tgfb1 iKO mice show cognitive deficits, supporting that precise spatial regulation of TGF-{beta}1 ligand derived from microglia is critical for the maintenance of brain homeostasis and normal cognitive function in the adult brain.