Lactic acid drives NLRP3 inflammasome activation and caspase-1-like cytokine cleavage via intracellular acidification.

Summary

This mechanistic study shows that intracellular lactic acidification is a potent signal for NLRP3 inflammasome activation and that lactic acid can directly cleave pro-IL-1β/IL-18 at caspase-1-like sites. In a murine cecal ligation and puncture sepsis model, systemic lactate exacerbated inflammation and worsened survival, linking hyperlactatemia to detrimental innate immune activation.

Key Findings

• NLRP3 activators (nigericin/ATP) increased lactic acid production and intracellular acidification, promoting ASC speck formation, caspase-1 activation, and IL-1β release.
• Elevated extracellular lactate impaired lactate efflux, further acidifying the cytosol; extracellular alkalinization abolished inflammasome activation.
• Intracellular acidification induced mitochondrial dysfunction, ROS, and PKR phosphorylation, facilitating PKR–NLRP3 interaction and inflammasome assembly.
• Lactic acid directly cleaved pro-IL-1β at Asp116 and processed pro-IL-18; systemic lactate worsened inflammation and survival in CLP sepsis.

Clinical Implications

Findings motivate evaluation of strategies that limit intracellular acidification (buffering, modulation of lactate production/efflux, or PKR/NLRP3 pathway inhibitors) and caution against iatrogenic lactate loading in severe sepsis until clinically validated.

Limitations

• Preclinical study without human validation; physiological relevance of lactate dosing requires careful calibration.
• No testing of targeted interventions (e.g., LDH inhibition or buffering) in survival-focused models.

Future Directions

Test pharmacologic or metabolic interventions that limit intracellular acidification or disrupt PKR–NLRP3 signaling in clinically relevant sepsis models and early-phase trials.