Critical Role of IL1R2-ENO1 Interaction in Inhibiting Glycolysis-Mediated Pyroptosis for Protection Against Lethal Sepsis.
Summary
The authors identify ENO1 as a binding partner of IL1R2 in macrophages, showing that IL1R2 suppresses ENO1 activity to curb glycolysis, GSDMD-mediated pyroptosis, and inflammation. IL1R2-deficient mice fare worse in sepsis, while ENO1 inhibition improves survival, positioning the IL1R2–ENO1 axis as a therapeutic checkpoint in immunometabolism.
Key Findings
- sIL1R2 is elevated in septic patients and mice; intracellular IL1R2 decreases during macrophage pyroptosis.
- Proteomics identifies ENO1 as an IL1R2-binding partner; IL1R2 suppresses ENO1 to inhibit glycolysis and GSDMD-mediated pyroptosis.
- IL1R2-deficient mice have worse sepsis outcomes; ENO1 inhibition reduces inflammation, organ injury, and improves survival.
Clinical Implications
Therapeutic targeting of the IL1R2–ENO1 interaction or ENO1 activity may reduce pyroptosis and organ injury in sepsis. sIL1R2 dynamics could serve as a biomarker to stratify patients for immunometabolic interventions.
Why It Matters
Defines a novel metabolic mechanism linking IL1R2 to glycolysis and pyroptosis, with direct survival benefit in murine sepsis through ENO1 inhibition. It advances druggable targets at the interface of inflammation and metabolism.
Limitations
- Human cohort size and clinical correlates are not detailed; translational pathways need formal trials
- Potential off-target effects and safety of ENO1 inhibition remain to be established
Future Directions
Develop small molecules/biologics that modulate IL1R2–ENO1; evaluate sIL1R2 as a stratification biomarker; test efficacy in larger animal models and early-phase sepsis trials.
Study Information
- Study Type
- Basic/Mechanistic research
- Research Domain
- Pathophysiology
- Evidence Level
- V - Mechanistic preclinical study with human biomarker observations and murine survival
- Study Design
- OTHER