Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure.

Aims: Iron deficiency (ID) is associated with adverse outcomes in heart failure (HF) but the underlying mechanisms are incompletely understood. Intracellular iron availability is secured by two mRNA-binding iron-regulatory proteins (IRPs), IRP1 and IRP2. We generated mice with a cardiomyocyte-targeted deletion of Irp1 and Irp2 to explore the functional implications of ID in the heart independent of systemic ID and anaemia. Methods and results: Iron content in cardiomyocytes was reduced in Irp-targeted mice. The animals were not anaemic and did not show a phenotype under baseline conditions. Irp-targeted mice, however, were unable to increase left ventricular (LV) systolic function in response to an acute dobutamine challenge. After myocardial infarction, Irp-targeted mice developed more severe LV dysfunction with increased HF mortality. Mechanistically, the activity of the iron-sulphur cluster-containing complex I of the mitochondrial electron transport chain was reduced in left ventricles from Irp-targeted mice. As demonstrated by extracellular flux analysis in vitro, mitochondrial respiration was preserved at baseline but failed to increase in response to dobutamine in Irp-targeted cardiomyocytes. As shown by 31P-magnetic resonance spectroscopy in vivo, LV phosphocreatine/ATP ratio declined during dobutamine stress in Irp-targeted mice but remained stable in control mice. Intravenous injection of ferric carboxymaltose replenished cardiac iron stores, restored mitochondrial respiratory capacity and inotropic reserve, and attenuated adverse remodelling after myocardial infarction in Irp-targeted mice but not in control mice. As shown by electrophoretic mobility shift assays, IRP activity was significantly reduced in LV tissue samples from patients with advanced HF and reduced LV tissue iron content. Conclusions: ID in cardiomyocytes impairs mitochondrial respiration and adaptation to acute and chronic increases in workload. Iron supplementation restores cardiac energy reserve and function in iron-deficient hearts.

Superior Suppressive Capacity of Skin Tregs Compared with Lung Tregs in a Model of Epicutaneous Priming.

We have previously shown that T helper type 2 (Th2)-polarized airway inflammation can facilitate priming to new antigens in the lungs, which we called "collateral priming". To investigate whether allergic skin inflammation can also facilitate priming toward new antigens, we developed an allergic skin inflammation model based on an allergic lung inflammation model. Mice were sensitized intraperitoneally toward the primary antigen, ovalbumin. Challenge was subsequently performed intranasally or epicutaneously with ovalbumin and a secondary antigen, keyhole limpet hemocyanin (KLH). Re-challenge consisted of local application of either antigen alone. Analysis of KLH-specific antibody responses, KLH-specific cytokines, and local inflammation demonstrated tolerance induction toward the secondary antigen in the skin, whereas in the lung priming had occurred. Flow-cytometric analysis revealed increased numbers of regulatory T cells (Tregs), increased cytotoxic T lymphocyte antigen-4 (CTLA-4) expression, and an enhanced suppressive capacity of Tregs from skin-draining lymph nodes when compared with Tregs from the lung-draining lymph nodes. Furthermore, depletion of Tregs resulted in restoration of collateral priming in the skin. These results demonstrate crucial local differences between the Treg function in the skin and lung to repetitive antigen exposure, which can decisively influence the immune response toward new antigens.