Lactic acid drives NLRP3 inflammasome activation and caspase-1-like cytokine cleavage via intracellular acidification - PubMed
19 hours ago
- #lactic acid
- #NLRP3 inflammasome
- #intracellular acidification
- NLRP3 activators like nigericin or ATP trigger lactic acid production and efflux in macrophages via lactate dehydrogenase.
- Intracellular lactic acid accumulation causes cytoplasmic acidification, promoting NLRP3 inflammasome activation and leading to ASC speck formation, caspase-1 activation, and IL-1β secretion.
- Extracellular lactic acid buildup impairs lactate efflux, worsening intracellular acidification and amplifying inflammasome activation, which can be prevented by alkalinization of the extracellular environment.
- Mechanistically, intracellular acidification induces mitochondrial dysfunction, ROS production, and PKR phosphorylation, facilitating PKR-NLRP3 interaction and inflammasome assembly through parallel pathways.
- Independently, lactic acid directly cleaves pro-IL-1β and pro-IL-18 into mature forms by mimicking caspase-1 activity, specifically at Asp116 in pro-IL-1β as confirmed by mass spectrometry.
- In a murine sepsis model, lactate administration increased inflammation, IL-1β levels, neutrophil infiltration, hypothermia, and worsened survival, highlighting lactic acid's role in promoting inflammation.