RESUMO
While TGF-ß signaling is essential for microglial function, the cellular source of TGF-ß1 ligand and its spatial regulation remains unclear in the 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 the activation of microglia featuring a dyshomeostatic transcriptome that resembles disease-associated, injury-associated, and aged microglia, suggesting microglial self-produced TGF-ß1 ligands are important in the adult CNS. Astrocytes in MG-Tgfb1 inducible (i)KO mice show a transcriptome profile that is closely aligned with an LPS-associated astrocyte profile. Additionally, using sparse mosaic single-cell microglia KO of TGF-ß1 ligand we established an autocrine mechanism for signaling. Here we show that MG-Tgfb1 iKO mice present cognitive deficits, supporting that precise spatial regulation of TGF-ß1 ligand derived from microglia is required for the maintenance of brain homeostasis and normal cognitive function in the adult brain.
Assuntos
Comunicação Autócrina , Cognição , Homeostase , Camundongos Knockout , Microglia , Fator de Crescimento Transformador beta1 , Animais , Microglia/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Camundongos , Cognição/fisiologia , Astrócitos/metabolismo , Transdução de Sinais , Encéfalo/metabolismo , Masculino , Transcriptoma , Camundongos Endogâmicos C57BL , Neurônios/metabolismoRESUMO
While TGF-ß signaling is essential for microglial function, the cellular source of TGF-ß 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-ß1 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-ß1 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-ß1 ligand, we established an autocrine mechanism for TGF-ß signaling. Importantly MG-Tgfb1 iKO 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.
