Abstract 18387: Interleukin 23-signaling Affects Infarct Healing and Promotes Wound Stabilisation in an Experimental Model of Myocardial Infarction by Controling the Function of Cardiac Fibroblasts
Introduction: Interleukin-23 coordinates together with other cytokines the adaptive immune response and its presence is important for the action of neutrophils, Th17 and regulatory T cells. We sought to determine the role of IL-23 in experimental myocardial infarction.
Methods: Myocardial infarction was induced by ligation of the left anterior descending artery in C57Bl6j and IL-23-knockout mice. Left ventricular function was examined by conductance catheter, expression of proinflammatory and antiinflammatory cytokines by PCR and inflammatory cells in the myocardium by immunohistochemistry after 4 and 30 days. Mortality was examined 30 days after myocardial infarction. Differentiation and phenotype of cardiac fibroblasts was assessed under basal conditions and after stimulation with interferon-γ (IFNγ).
Results: Endystolic and enddiastolic LV-volumes were higher in the IL-23-knockout mice 4 days after myocardial infarction (30%, p=0.05 and 35%, p=0.02 respectively). Expression of IL-1β was upregulated by 50% (p=0.006) and IFN-γ by 100% (p=0.05) in the infarction zone in the IL-23-knockout mice. Migration of neutrophils and macrophages in the infarcted area was higher in the IL23-knockout mice (by 43%, p=0.04 and 41%, p=0.03 respectively). IL-23-knockout mice showed a lower 30-days survival rate due to increased ventricular rupture (63% vs. 24%, p=0.036). Expression of α-smooth muscle actin (α-SMA, 2fold increase, p<0.05), collagen I (2.1fold increase, p<0.05) and III (1.9fold increase, p<0.01) as markers of fibrosis and activation of myofibroblasts were significantly higher in the infarction area in the wild type mice 30 days after infarction. Cardiac fibroblasts isolated from the infarcted and non-infarcted zones showed a 50% lower expression of αSMA, 30% lower collagen I and 20% lower collagen III (p<0.05) in the IL23KO-mice. Stimulation of cardiac fibroblasts with IFNγ led to a downregulation of αSMA and collagen I and upregulation of the proinflammatory chemokines CCL2 and CXCL10.
Conclusions: IL23 controls the expression of IFNγ in the heart after myocardial infarction and induces the differentiation of cardiac fibroblasts into myofibroblasts promoting healing and wound stabilization.
- © 2012 by American Heart Association, Inc.