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.
Curated pathway from expert analysis
flowchart TD
A["Astrocyte-Derived TGF-beta1<br/>Anti-inflammatory Ligand"]
B["TGFBR2/TGFBR1 Complex<br/>Microglial Receptor Activation"]
C["SMAD2/3 Phosphorylation<br/>SMAD4 Corepressor Assembly"]
D["RelA/p300 Displacement<br/>NF-kB Enhancer Rewiring"]
E["TNF/IL1B/IL6 Suppression<br/>Trained Immunity Memory Reset"]
F["Homeostatic Microglial State<br/>Inflammatory Tone Reduced"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style F fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for TGFBR1 yet. Search RCSB →
Median TPM across 13 brain regions for TGFBR1/TGFBR2 → SMAD4 → SMAD2/3 from GTEx v10.
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for TGFBR1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF microglial SMAD2/3 is genetically ablated (Cx3cr1-CreER × Smad2/3 flox/flox) prior to TGF-β1 preconditioning, THEN the expected suppression of LPS-induced TNF-α, IL-1β, and IL-6 release will be abo | TGF-β1 preconditioning fails to suppress inflammatory cytokine release in SMAD2/3-deficient microglia; cytokine levels remain elevated (TNF-α >500 pg/mL, IL-1β | — no observation — | pending | 0.70 |
| IF CRISPR-mediated epigenetic blockade (dCas9-KRAB) prevents TGF-β1–induced H3K27ac reduction at the TNF, IL1B, and IL6 enhancer loci, THEN the anti-inflammatory reprogramming effect of TGF-β1 will be | Loss of H3K27ac depletion at inflammatory gene enhancers preserves trained immunity phenotype; CRISPR-targeted microglia show TNF-α, IL-1β, and IL-6 release com | — no observation — | pending | 0.65 |