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

Nat Commun. 2016 Nov 24;7:13344. doi: 10.1038/ncomms13344.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Antirheumatic Agents / pharmacology
  • Arrhythmias, Cardiac / etiology
  • Arrhythmias, Cardiac / immunology
  • Arrhythmias, Cardiac / metabolism
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Caspase 1 / metabolism
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / immunology*
  • Diabetes Mellitus, Experimental / metabolism
  • Inflammasomes / antagonists & inhibitors
  • Interleukin 1 Receptor Antagonist Protein / pharmacology
  • Interleukin-1beta / genetics
  • Interleukin-1beta / immunology*
  • Interleukin-1beta / metabolism
  • Macrophages / immunology*
  • Mice
  • Mice, Transgenic
  • Myocardial Contraction
  • Myocytes, Cardiac / immunology
  • Myocytes, Cardiac / metabolism*
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology*
  • Potassium / metabolism
  • Receptors, Interleukin-1 / antagonists & inhibitors
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / immunology
  • Tachycardia, Ventricular / etiology
  • Tachycardia, Ventricular / immunology*
  • Tachycardia, Ventricular / metabolism
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / immunology*

Substances

  • Antirheumatic Agents
  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Receptors, Interleukin-1
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Casp1 protein, mouse
  • Caspase 1
  • Potassium
  • Calcium