IL-1ß 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)-1ß levels. Our study shows that 15-day IL-1ß injections sensitize mice to AF, inducing fibrosis, ß-pleated protein accumulation in the atria, and systemic inflammation resembling AF patients. Increased caspase-1 and IL-1ß 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-1ß 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-1ß 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-1ß-driven AF etiology mediated by IL-1R in cardiac resident macrophages and caspase-1, offering insights into therapeutic targets and distinct AF etiologies. Overall design: Mice were injected or not with IL-1b or saline for 15 consecutive days. Atrial from both groups were analyzed by RNAsec.

心房颤动（Atrial fibrillation, AF）作为一种常见的心律失常，在白介素-1β（interleukin-1β, IL-1β）水平升高的患者中患病率更高。本研究证实，为期15天的IL-1β注射可使小鼠对AF易感，并诱发心房纤维化、心房内β折叠蛋白沉积以及与AF患者相似的全身性炎症。左心房内半胱天冬酶-1（caspase-1）与IL-1β的成熟水平上调，且常驻巨噬细胞中Il1b与Casp1的转录水平升高——这一过程依赖于白介素-1受体（IL-1R）——提示存在正反馈调控环路。IL-1β可缩短动作电位（action potentials, APs），加速动作电位与钙瞬变的恢复过程，而AF易感性依赖于动作电位缩短、半胱天冬酶-1与IL-1R的存在。Cre-Lox基因敲除模型实验显示，IL-1β信号通路的发挥依赖于巨噬细胞而非心肌细胞中的IL-1R。尽管缺乏募集性巨噬细胞的Ccr2基因敲除（Ccr2-/-）小鼠仍对AF易感，但心脏常驻巨噬细胞中IL-1R缺失的小鼠则可获得AF保护。本研究揭示了一种由IL-1β驱动的新型AF发病机制，该机制由心脏常驻巨噬细胞中的IL-1R与半胱天冬酶-1介导，为AF的治疗靶点发掘与不同发病亚型的区分提供了全新见解。实验整体设计：将小鼠连续15天注射IL-1β或生理盐水作为对照，随后对两组小鼠的心房组织进行RNA测序。