Global IL4Rα blockade exacerbates heart failure after an ischemic event in mice and humans.

Ischemic heart failure continues to be a highly prevalent disease among westernized countries and there is great interest in understanding the mechanisms preventing or exacerbating disease progression. The literature suggests an important role for the activation of interleukin-13 or interleukin-4 signaling in improving ischemic heart failure outcomes after myocardial infarction in mice. Dupilumab, a neutralizing antibody that inhibits the shared IL13/IL4 receptor subunit IL4Rα, is widely used for conditions such as ectopic dermatitis in humans.

IL-13 promotes functional recovery after myocardial infarction via direct signaling to macrophages.

There is great interest in identifying signaling pathways that promote cardiac repair after myocardial infarction (MI). Prior studies suggest a beneficial role for IL-13 signaling in neonatal heart regeneration; however, the cell types mediating cardiac regeneration and the extent of IL-13 signaling in the adult heart after injury are unknown. We identified an abundant source of IL-13 and the related cytokine, IL-4, in neonatal cardiac type 2 innate lymphoid cells, but this phenomenon declined precipitously in adult hearts.

Myofibroblast Ccn3 is regulated by Yap and Wwtr1 and contributes to adverse cardiac outcomes.

Introduction: While Yap and Wwtr1 regulate resident cardiac fibroblast to myofibroblast differentiation following cardiac injury, their role specifically in activated myofibroblasts remains unexplored.

Methods: We assessed the pathophysiological and cellular consequence of genetic depletion of Yap alone ( ; ) or Yap and Wwtr1 ( ; ; ) in adult mouse myofibroblasts following myocardial infarction and identify and validate novel downstream factors specifically in cardiac myofibroblasts that mediate pathological remodeling.

Results: Following myocardial infarction, depletion of Yap in myofibroblasts had minimal effect on heart function while depletion of Yap/Wwtr1 resulted in smaller scars, reduced interstitial fibrosis, and improved ejection fraction and fractional shortening.

Interleukin 4/13 signaling in cardiac regeneration and repair.

Interleukin 4 (IL4) and interleukin 13 (IL13) are closely related cytokines that have been classically attributed to type II immunity, namely, differentiation of T-helper 2 (T2) cells and alternative activation of macrophages. Although the role of IL4/13 has been well described in various contexts such as defense against helminth parasites, pathogenesis of allergic disease, and several models of wound healing, relatively little is known about the role of IL4/13 in the heart following injury. Emerging literature has identified various roles for IL4/13 in animal models of cardiac regeneration as well as in the adult mammalian heart following myocardial injury.

The Evolving Roles of Cardiac Macrophages in Homeostasis, Regeneration, and Repair.

Macrophages were first described as phagocytic immune cells responsible for maintaining tissue homeostasis by the removal of pathogens that disturb normal function. Historically, macrophages have been viewed as terminally differentiated monocyte-derived cells that originated through hematopoiesis and infiltrated multiple tissues in the presence of inflammation or during turnover in normal homeostasis. However, improved cell detection and fate-mapping strategies have elucidated the various lineages of tissue-resident macrophages, which can derive from embryonic origins independent of hematopoiesis and monocyte infiltration.

IL4Rα signaling promotes neonatal cardiac regeneration and cardiomyocyte cell cycle activity.

Neonatal heart regeneration depends on proliferation of pre-existing cardiomyocytes, yet the mechanisms driving regeneration and cardiomyocyte proliferation are not comprehensively understood. We recently reported that the anti-inflammatory cytokine, interleukin 13 (IL13), promotes neonatal cardiac regeneration; however, the signaling pathway and cell types mediating this regenerative response remain unknown. Here, we hypothesized that expression of the type II heterodimer receptor for IL13, comprised of IL4Rα and IL13Rα1, expressed directly on cardiomyocytes mediates cardiomyocyte cell cycle and heart regeneration in neonatal mice.

Acute and chronic changes in the control of breathing in a rat model of bronchopulmonary dysplasia.

Infants born very prematurely (<28 wk gestation) have immature lungs and often require supplemental oxygen. However, long-term hyperoxia exposure can arrest lung development, leading to bronchopulmonary dysplasia (BPD), which increases acute and long-term respiratory morbidity and mortality. The neural mechanisms controlling breathing are highly plastic during development.

The Impact of Midcervical Contusion Injury on Diaphragm Muscle Function.

Midcervical contusion injuries disrupt descending ipsilateral excitatory bulbospinal projections to phrenic motoneurons, compromising ventilation. We hypothesized that a unilateral contusion injury at C3 versus C5 would differentially impact phrenic activity reflecting more prominent disruption of ipsilateral descending excitatory drive to more caudal segments of the phrenic motor pool with more cranial injuries. Phrenic motoneuron counts and evidence of diaphragm muscle denervation at individual neuromuscular junctions (NMJ) were evaluated at 14 days post-injury after unilateral contusion injury (100 kDynes).