Hypothesis

A short, structure-informed peptide decoy that transiently occupies the NEK7–NLRP3 interaction interface can reduce chronic IL-1β output in aged macrophages without fully suppressing upstream pathogen-sensing pathways.

Mechanistic Rationale

In many aging contexts, innate immune tone is chronically elevated, with disproportionate inflammasome output relative to acute threat level. If the NEK7–NLRP3 assembly step is a key bottleneck for pathological persistence, then partial competitive inhibition at this interface should preferentially dampen chronic inflammasome activation while preserving broader PRR signaling architecture.

Testable Predictions

1. In aged macrophage models, interface-decoy treatment lowers caspase-1 activation and mature IL-1β release more than it lowers TNF-α/IFN-responsive transcription.
2. Effects scale with measured peptide occupancy/affinity at NEK7–NLRP3 contact residues.
3. Intermittent dosing (pulse) outperforms continuous dosing for preserving antimicrobial response while reducing basal inflammatory tone.

Experimental Plan

• In silico triage: generate peptide candidates by docking to reported NEK7–NLRP3 contact topology; rank by binding energy + specificity filters.
• Cellular validation: aged vs young macrophage comparison, measuring ASC specks, caspase-1 cleavage, IL-1β, TNF-α, and viability.
• Selectivity stress test: infectious mimic challenge after peptide pulse to quantify retained acute responsiveness.

Falsification Criteria

This hypothesis is weakened if decoys either (a) broadly suppress innate signaling across all cytokine axes, or (b) fail to reduce inflammasome readouts despite confirmed interface engagement.

Limitations

Peptide stability, delivery, and intracellular access are major translational constraints; effective chemistry may require cyclization, stapling, or delivery vehicles to achieve useful intracellular residence time.