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

Summary

Intracellular lactic acidification acts as a metabolic trigger for NLRP3 inflammasome activation by promoting mitochondrial dysfunction and PKR-mediated assembly, while lactic acid can also directly cleave pro-IL-1β/IL-18 at canonical caspase-1 sites. In vivo, systemic lactate worsened inflammation and survival in polymicrobial sepsis, highlighting lactate as both an upstream danger signal and a non-enzymatic cytokine-processing agent.

Key Findings

• Intracellular lactic acidification promotes NLRP3 inflammasome activation, ASC specking, caspase-1 activation, and IL-1β release.
• Extracellular alkalinization prevents acidification and abolishes inflammasome activation, indicating pH-dependence.
• Lactic acid directly cleaves pro-IL-1β at Asp116 and pro-IL-18, mimicking caspase-1 specificity.
• Systemic lactate exacerbates inflammation and mortality in a murine cecal ligation and puncture sepsis model.

Clinical Implications

The findings suggest that targeting intracellular acidification, lactate handling, PKR, or NLRP3 could attenuate IL-1β/IL-18–driven inflammation in sepsis and inflammatory disorders. Clinicians should be cautious with high-lactate contexts and consider buffering strategies in critical care; aesthetic use of high-concentration lactic acid may warrant prudence in inflamed skin.

Limitations

• Translational relevance from murine sepsis and high-lactate conditions to human disease and tissue microenvironments remains to be defined.
• Quantitative exposure thresholds for lactate-induced cytokine processing in human tissues are not established.

Future Directions

Define lactate thresholds and kinetics in human tissues; test buffering, PKR, or NLRP3 inhibitors clinically; assess implications for dermatologic procedures using alpha-hydroxy acids.