Aerobic glycolysis promotes NLRP3 inflammasome activation via NLRP3 lactylation.
Summary
Lactate generated by aerobic glycolysis directly modifies NLRP3 via AARS2-mediated lactylation at K24 and K565, enhancing ASC recruitment and inflammasome assembly to drive pyroptosis. Inhibiting lactate production reduced inflammatory responses in a polymicrobial sepsis model.
Key Findings
- Endogenous lactate promotes NLRP3 inflammasome assembly by facilitating ASC recruitment.
- NLRP3 is lactylated by AARS2 at K24 and K565, enhancing inflammasome activation.
- In vivo inhibition of lactate production alleviates inflammation in polymicrobial sepsis.
Clinical Implications
Supports exploration of glycolysis/LDH inhibitors or modulators of protein lactylation/AARS2 as strategies to temper excessive inflammasome activity in sepsis.
Why It Matters
Defines a direct post-translational modification (lactylation) of NLRP3 as a metabolic checkpoint for inflammasome activation, opening avenues to target immunometabolism in sepsis.
Limitations
- Specificity and druggability of AARS2-mediated lactylation remain to be established in vivo.
- Systemic inhibition of glycolysis may carry safety risks in critically ill patients.
Future Directions
Develop selective modulators of protein lactylation or NLRP3–AARS2 interaction; define therapeutic windows for metabolic interventions in sepsis.
Study Information
- Study Type
- Experimental mechanistic study (preclinical)
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic work in macrophages with in vivo validation in a sepsis model.
- Study Design
- OTHER