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bioRxiv · 10.1101/2023.07.05.547814

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

Bedolla, A. M.·Wegman, E.·Weed, M.·Paranjpe, A.·Alkhimovitch, A.·Ifergan, I.·McClain, L.·Luo, Y.
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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.

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Bedolla, A. M., Wegman, E., Weed, M., Paranjpe, A., Alkhimovitch, A., Ifergan, I., McClain, L., Luo, Y.. 2023-07-07. Microglia-derived TGF-β1 ligand maintains microglia homeostasis via autocrine mechanism and is critical for normal cognitive function in adult mouse brain. https://doi.org/10.1101/2023.07.05.547814

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