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

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia worldwide, significantly impairs quality of life and increases the risk of major cardiovascular events. Since overactivation of NLRP3 in cardiomyocytes induces AF in mice, IL-1β is a potential mediator between sterile inflammation and AF. Thus, our study aimed to test the hypothesis that IL-1β can sensitize mice to AF through activation of resident macrophages. All animal protocols were aproved by animal ethics comitee (CEUA 169/18).  We administered daily subcutaneous IL-1β or saline injections to mice, and tested AF susceptibility by transesophageal electric stimulation. AF was more frequently observed in IL-1β-injected mice (Saline 2/12 vs IL-1β 9/12, p = 0.012). Left atrial tissue from IL-1β-injected mice exhibited increased fibrosis and β-pleated protein deposition, as revealed by second harmonic generation and Fourier transformed infrared spectroscopy. Furthermore, IL-1β-injected mice displayed enhanced caspase-1 and IL-1β maturation in the left atrium. Cardiac resident macrophages from IL-1β-injected mice increased transcription of Il1b and casp1, dependent on IL-1 receptor (IL-1R), suggesting a positive feedback loop. IL-1β Injections shortened action potentials (APs), and accelerated APs and Ca²⁺ transient restitution. AF susceptibility was dependent on shortened APs, caspase-1 and IL-1R expression. Using Cre-Lox knockout mice targeting IL-1R, we demonstrated that IL-1β- increased susceptibility to AF requires IL-1R signaling in macrophages but not in cardiomyocytes. CCR2^-/- mice, lacking recruited macrophages, remained susceptible to AF in response to IL-1β, whereas mice with  IL-1R-devoided resident macrophages were resistant to AF. This study identifies a novel AF etiology driven by IL-1β signaling trough IL-1R in resident macrophages and dependent on caspase-1. These findings highlight new therapeutic targets and emphasize the importance of immune cells in cardiac pathophysiology.