Macrophage WEE1 Directly Binds to and Phosphorylates NF-κB p65 Subunit to Induce Inflammatory Response and Drive Atherosclerosis.
Summary
This mechanistic study identifies WEE1 as a macrophage kinase that directly binds NF-κB p65 and phosphorylates S536, amplifying inflammatory signaling and atherogenesis. Genetic deletion or pharmacologic inhibition of WEE1 attenuated inflammation and atherosclerosis in mice, highlighting WEE1 as a druggable upstream regulator of NF-κB.
Key Findings
- Macrophage WEE1 is phosphorylated (S642) in human and mouse atherosclerotic tissues.
- WEE1 phosphorylation (not expression) mediates oxLDL-induced macrophage inflammation.
- Macrophage-specific WEE1 deletion or pharmacologic inhibition reduces inflammation and atherosclerosis in mice.
- WEE1 directly binds NF-κB p65 and phosphorylates S536, activating NF-κB signaling.
Clinical Implications
While preclinical, the work supports evaluating WEE1 inhibitors for anti-inflammatory atheroprotection and encourages biomarker development (p65 S536 phosphorylation) to select responders.
Why It Matters
Revealing WEE1 as a direct upstream kinase for NF-κB p65 provides a novel, actionable target in atherosclerosis with immediate translational relevance given existing WEE1 inhibitors.
Limitations
- Preclinical models; lack of human interventional validation
- Potential off-target and safety considerations with systemic WEE1 inhibition
Future Directions
Test WEE1 inhibitors in atherosclerosis models with cardiovascular endpoints; develop macrophage-targeted delivery; validate p65 S536 phosphorylation as a pharmacodynamic biomarker in human plaques.
Study Information
- Study Type
- Basic/Mechanistic Research
- Research Domain
- Pathophysiology
- Evidence Level
- IV - Preclinical mechanistic evidence from animal models and human tissues
- Study Design
- OTHER