Macrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice

Abstract

Diabetes mellitus (DM) encompasses a multitude of secondary disorders, including heart disease. One of the most frequent and potentially life threatening disorders of DM-induced heart disease is ventricular tachycardia (VT). Here we show that toll-like receptor 2 (TLR2) and NLRP3 inflammasome activation in cardiac macrophages mediate the production of IL-1β in DM mice. IL-1β causes prolongation of the action potential duration, induces a decrease in potassium current and an increase in calcium sparks in cardiomyocytes, which are changes that underlie arrhythmia propensity. IL-1β-induced spontaneous contractile events are associated with CaMKII oxidation and phosphorylation. We further show that DM-induced arrhythmias can be successfully treated by inhibiting the IL-1β axis with either IL-1 receptor antagonist or by inhibiting the NLRP3 inflammasome. Our results establish IL-1β as an inflammatory connection between metabolic dysfunction and arrhythmias in DM.

Macrophages Facilitate Electrical Conduction in the Heart

“…Macrophages change in phenotype and number in response to myocardial infarction (Swirski and Nahrendorf, 2013) and heart failure (Sager et al, 2016), conditions associated with sudden cardiac death as a result of ventricular arrhythmias (Bunch et al, 2007). Moreover, diabetes-induced activation of cardiac macrophages induces arrhythmias through IL-1β production (Monnerat et al, 2016). Other inflammatory diseases of the heart, including Chagas, Lyme, sarcoid and myocarditis cause conduction abnormalities.…”

Diabetic Cardiomyopathy: An Immunometabolic Perspective

“…The loss of Ly6C high monocytes prevents hypertension-induced cardiac fibrosis and improves cardiac function after MI (141, 153, 154). Monnerat et al suggest that diabetes enhances IL1β production from cardiac MHC II high pro-inflammatory macrophages through activation of TLR2–NLRP3 inflammasome axis (155). The increased level of IL1β leads to a reduction in potassium current and an increase in calcium sparks in cardiomyocytes, which cause cardiac arrhythmias (156).…”

P2X7 receptor in cardiovascular disease: The heart side

“…The induction of inflammasome formation after a heart ischaemic injury occurs in cardiac fibroblasts, endothelial cells, or leukocytes, resulting in the secretion of IL‐1β, but not in cardiomyocytes . IL‐1β can also be secreted by cardiac macrophages in response to sterile inflammation induced by diabetes mellitus in response to TLR‐2 and NLRP3 induction . IL‐1β, as TNFα and IL‐6, can be arrhythmogenic by directly impacting cardiomyocyte ion channels .…”

“…139,159 IL-1β can also be secreted by cardiac macrophages in response to sterile inflammation induced by diabetes mellitus in response to TLR-2 and NLRP3 induction. 160 IL-1β, as TNFα and IL-6, can be arrhythmogenic by directly impacting cardiomyocyte ion channels. 161,162 IL-1β reduces the transient outward K + current, alters expression and function of calcium channels and calcium-regulating proteins, leads to functional desensitization of the β-adrenergic receptors and can cause prolongation of the action potential duration 160,[163][164][165][166] (Figure 2).…”

“…160 IL-1β, as TNFα and IL-6, can be arrhythmogenic by directly impacting cardiomyocyte ion channels. 161,162 IL-1β reduces the transient outward K + current, alters expression and function of calcium channels and calcium-regulating proteins, leads to functional desensitization of the β-adrenergic receptors and can cause prolongation of the action potential duration 160,[163][164][165][166] (Figure 2). On the other hand, in cardiomyocytes, the NLRP3 assembly activates caspase 1 and induces pyroptosis but does not cause the secretion of high levels of IL-1β.…”