Adult microglial TGFβ1 is required for microglia homeostasis via an autocrine mechanism to maintain cognitive function in mice

Alicia Bedolla, Elliot Wegman, Max Weed, Messiyah K. Stevens, Kierra Ware, Aditi Paranjpe, Anastasia Alkhimovitch, Igal Ifergan, Aleksandr Taranov, Joshua D. Peter, Rosa Maria Salazar Gonzalez, J. Elliott Robinson, Lucas McClain, Krishna M. Roskin, Nigel H. Greig and Yu Luo ()
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Alicia Bedolla: University of Cincinnati
Elliot Wegman: University of Cincinnati
Max Weed: University of Cincinnati
Messiyah K. Stevens: Vanderbilt University
Kierra Ware: University of Cincinnati
Aditi Paranjpe: Cincinnati Children’s Hospital Medical Center
Anastasia Alkhimovitch: University of Cincinnati
Igal Ifergan: University of Cincinnati
Aleksandr Taranov: University of Cincinnati
Joshua D. Peter: University of Cincinnati
Rosa Maria Salazar Gonzalez: Cincinnati Children’s Hospital Medical Center
J. Elliott Robinson: Cincinnati Children’s Hospital Medical Center
Lucas McClain: University of Cincinnati
Krishna M. Roskin: Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine
Nigel H. Greig: National Institutes of Health
Yu Luo: University of Cincinnati

Nature Communications, 2024, vol. 15, issue 1, 1-25

Abstract: Abstract While TGF-β signaling is essential for microglial function, the cellular source of TGF-β1 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-β1 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-β1 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-β1 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-β1 ligand derived from microglia is required for the maintenance of brain homeostasis and normal cognitive function in the adult brain.

Date: 2024
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DOI: 10.1038/s41467-024-49596-0

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