Background: The ‘NACHT, LRR and PYD domains binding protein-3’ (NLRP3) inflammasome is upregulated in patients with atrial fibrillation (AF), potentially contributing to atrial arrhythmogenesis.
Objective: To assess if AF-mimicking high atrial rate contributes to NLRP3-inflammasome activation in atrial cardiomyocytes and to dissect the contribution of “canonical” (caspase-1, Casp1) and “non-canonical” (caspase-11, Casp11) pathways to NLRP3-inflammasome activation.
Methods: We established an in vitro tachypacing (5 Hz, 15mV/5ms) model in murine HL-1 atrial cardiomyocytes and assessed the NLRP3-inflammasome components by qPCR and Western Blot.
Results: 5 Hz-pacing increased NLRP3 mRNA and protein levels, indicating transcriptional priming (Figure 1A). Protein levels of the other NLRP3 components were either unchanged (caspase-1) or reduced (‘apoptosis-associated speck-like protein containing a CARD’, ASC). Interleukin-1β maturation was unaffected, suggesting the “canonical” NLRP3 inflammasome pathway is not activated. Gasdermin D (GSDMD) cleavage with subsequent membrane-pore formation via its N-terminal fragment promotes the release of interleukin-1β and was significantly increased at 5 Hz (Figure 1B). Cleavage (activation) of the GSGMD regulating Casp11 was also significantly enhanced, indicating activation of the “non-canonical” NLRP3 inflammasome with pacing at 5 Hz.
Conclusion: We identify high atrial rate mimicking AF as a driver of the “non-canonical” NLRP3 inflammasome in atrial cardiomyocytes. The NLRP3 inflammasome, for which therapeutic options are available, might constitute a novel anti-AF target.