Time-restricted antagonism of inflammatory cytokine receptors (IL-1R, TNFR) during peak inflammatory phases to break positive feedback loops maintaining microglial priming
Curated pathway from expert analysis
flowchart TD
A["Neurodegeneration Triggers<br/>Amyloid Tau Aggregates"]
B["DAM Microglial Activation<br/>Peak Inflammatory Phase"]
C["IL-1beta TNF-alpha Release<br/>Cytokine Positive Feedback Loop"]
D["IL-1R1 IL1R1 Signaling<br/>MyD88 NF-kappaB Activation"]
E["TNFRSF1A TNFR1 Signaling<br/>Inflammatory Gene Program"]
F["Microglial Priming Maintained<br/>Sustained Neuroinflammation"]
G["Time-Restricted IL1R TNFR Antagonism<br/>Breaks Positive Feedback"]
H["Homeostatic Microglial State Restored<br/>Inflammation Resolved"]
A --> B
B --> C
C --> D
C --> E
D --> F
E --> F
F -.->|"broken by"| G
G --> H
style F fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style H fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for IL1R1 yet. Search RCSB →
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 IL1R1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF IL1R1/TNFRSF1A antagonists are administered during pharmacokinetically-defined peak inflammatory phases (detected by rising IL-6 plasma levels) rather than at baseline or chronic phases, THEN micro | Microglial priming scores will decrease by >40% (CD68 mean fluorescent intensity normalized to Iba1) in the time-restricted antagonist group compared to vehicle | — no observation — | pending | 0.72 |
| IF IL1R1 is selectively antagonized during verified peak inflammatory phases while TNFRSF1A signaling remains intact (and vice versa), THEN single-receptor blockade during peak inflammation will parti | Dual-receptor peak-phase blockade will reduce Trem2-positive primed microglia frequency by >50% and lower Nlrp3 inflammasome活化 (caspase-1 activity assay, ASC sp | — no observation — | pending | 0.68 |