IL-1β sensitizes to atrial fibrillation acting through resident macrophages and caspase-1 expression

Atrial fibrillation (AF), a common cardiac arrhythmia, is more prevalent in patients with elevated interleukin (IL)-1β levels. Our study shows that 15-day IL-1β injections sensitize mice to AF, inducing fibrosis, β-pleated protein accumulation in the atria, and systemic inflammation resembling AF patients. Increased caspase-1 and IL-1β maturation in the left atrium and elevated Il1b and Casp1 transcription in resident macrophages—dependent on IL-1 receptor (IL-1R)—indicate a positive feedback loop. IL-1β shortened action potentials (APs), accelerating AP and Ca2+ transient restitution, and AF sensitivity required shortened APs, caspase-1, and IL-1R. Cre-Lox knockout models revealed IL-1β signaling relies on IL-1R in macrophages, not cardiomyocytes. While Ccr2-/- mice, lacking recruited macrophages, remained AF-susceptible, mice with IL-1R deletion in cardiac resident macrophages were protected. We present a novel IL-1β-driven AF etiology mediated by IL-1R in cardiac resident macrophages and caspase-1, offering insights into therapeutic targets and distinct AF etiologies. Mice were injected or not with IL-1b or saline for 15 consecutive days. Atrial from both groups were analyzed by RNAsec.