Cigarette smoking induces NLRP3 inflammasome activation in patients with atrial fibrillation

Atrial fibrillation (AF) represents one of the most common arrhythmias seen clinically and is associated with a significant increase in morbidity and mortality. One of the main contributors to the pathophysiology for the initiation, progression, and persistence of AF is inflammation. Inflammatory infiltrates and increased serum levels of proinflammatory cytokines have been demonstrated in animal models and patients with AF. AF progression is associated with increased levels of these proinflammatory cytokines. Cigarette smoking is associated with an increased risk of AF. Moreover, cigarette smoke is known to increase inflammation and proinflammatory cytokines including interleukin (IL)-1β, IL-18, and tumor necrosis factor-α (TNF-α). Therefore, it is of great clinical importance to elucidate the underlying mechanisms contributing to smoking-induced inflammation in patients with AF. A critical amplifier of inflammation is the NLRP3 inflammasome, which is increased in patients with AF. Here, we identify critical upstream mechanisms leading to NLRP3 inflammasome activation via endoplasmic reticulum stress in atrial tissues from patients with AF and human-induced pluripotent stem cell-atrial cardiomyocytes. These findings reveal important mechanistic insights into possible upstream targets in controlling excessive inflammation due to smoking in patients with AF.<b>NEW & NOTEWORTHY</b> This study demonstrates that atrial fibrillation patients who have had a history of cigarette smoking within the past year exhibit increased inflammation amplified by NLRP3 inflammasome activation and heightened endoplasmic reticulum (ER) stress. Our findings suggest that ER stress acts as an upstream activator of the NLRP3 inflammasome, presenting a potential therapeutic target to mitigate the excessive inflammation observed in patients with AF with smoking exposure.