IL-1β enhances susceptibility to atrial fibrillation in mice by acting through resident macrophages and promoting caspase-1 expression

Atrial fibrillation (AF) is more prevalent in patients with elevated interleukin (IL)-1β levels. Here we show that daily administration of IL-1β for 15 days sensitizes mice to AF, leading to fibrosis, accumulation of β-pleated sheet proteins in the left atrium, and systemic inflammation, resembling the pathophysiological changes observed in patients with AF. IL-1β administration creates a positive feedback loop, dependent on the IL-1 receptor (IL-1R) activity in cardiac resident macrophages. This results in increased caspase-1 maturation in the left atrium and elevated Il1b and Casp1 transcription in atrial macrophages. IL-1β treatment accelerated action potential and Ca2+ restitution in the left atrium, leading to action-potential shortening. This, along with increased caspase-1 maturation and IL-1R signaling, was essential for inducing AF. Lack of IL-1R in macrophages, but not cardiomyocytes, prevented IL-1β-induced AF sensitivity. By depleting recruited macrophages or deleting IL-1R specifically in cardiac resident macrophages, we further demonstrate that IL-1β/IL-1R signaling in these resident macrophages is responsible for increased AF susceptibility. These findings offer insights into the therapeutic potential of targeting IL-1β/IL-1R signaling in patients with AF and emphasize the importance of recognizing different underlying causes in this patient group. Moreno-Loaiza et al. found that interleukin-1β, acting upon cardiac resident macrophages, promotes atrial fibrillation in mice, and this mechanism may represent a common pathway connecting various risk factors to this arrhythmia.