Mechanistic description
Astrocyte-derived TGF-β1 engages microglial TGFBRII/TGFBRI complex, activating SMAD2/3 corepressor complexes that displace RelA/p300 coactivators at NF-κB-dependent promoters (TNF, IL1B, IL6). This mechanism rewires trained microglia to a homeostatic state by disrupting epigenetic memory at inflammatory gene enhancers. Supported by landmark ALS and Parkinson’s disease studies showing TGF-β-driven anti-inflammatory microglial phenotypes.
Evidence for (4)
TGF-β as key astrocyte-derived factor promoting anti-inflammatory microglial phenotype in ALS
Astrocytes release neuroprotective factors including TGF-β in reactive states
TGF-β1 suppresses microglial NLRP3 inflammasome in Parkinson's models
Reduced TGF-β signaling in Alzheimer's post-mortem microglia correlates with disease severity (AMP-AD)
Evidence against (3)
TGF-β1 can maintain microglial activation in certain contexts; effects are dose- and context-dependent
TGF-β receptor signaling may suppress homeostatic surveillance (CX3CR1 downregulation), increasing infection vulnerability
SMAD2/3 binding sites are sparse at classical trained enhancer loci (TNF, IL6)
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