Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction

Area of Science:

• Cardiovascular Science
• Inflammation Research
• Microbiome Metabolism

Background:

• Plasma trimethylamine-N-oxide (TMAO) is linked to atherosclerosis and cardiovascular diseases (CVD).
• The precise molecular mechanisms by which TMAO contributes to CVD remain unclear.
• This study investigates TMAO's role in NLRP3 inflammasome activation and endothelial injury.

Purpose of the Study:

• To determine if TMAO induces NLRP3 inflammasome formation and activation.
• To investigate TMAO's contribution to endothelial injury and atherogenesis.
• To elucidate the mechanisms of TMAO-induced NLRP3 inflammasome activation.

Main Methods:

• Assessed inflammasome formation via confocal microscopy.
• Measured caspase-1 activity, IL-1β production, and cell permeability.
• Utilized in vitro cell cultures and in vivo mouse models with TMAO infusion.

Main Results:

• TMAO increased NLRP3 inflammasome components, caspase-1 activity, IL-1β production, and cell permeability in endothelial cells.
• Caspase-1 inhibition or NLRP3 knockdown abrogated TMAO's effects.
• TMAO-induced inflammasome activation involved redox regulation and lysosomal dysfunction.
• In vivo, TMAO increased inflammasome formation and IL-1β in mouse carotid artery intima.

Conclusions:

• TMAO-induced NLRP3 inflammasome formation and activation initiate endothelial inflammatory responses.
• This process contributes to endothelial dysfunction, a critical step in atherogenesis.
• TMAO represents a significant link between gut microbiota and cardiovascular pathology.