Hypereosinophilia causes progressive cardiac pathologies in mice

Abstract

Hypereosinophilic syndrome is a progressive disease with extensive eosinophilia that results in organ damage. Cardiac pathologies are the main reason for its high mortality rate. A better understanding of the mechanisms of eosinophil-mediated tissue damage would benefit therapeutic development. Here, we describe the cardiac pathologies that developed in a mouse model of hypereosinophilic syndrome. These IL-5 transgenic mice exhibited decreased left ventricular function at a young age which worsened with age. Mechanistically, we demonstrated infiltration of activated eosinophils into the heart tissue that led to an inflammatory environment. Gene expression signatures showed tissue damage as well as repair and remodeling processes. Cardiomyocytes from IL-5Tg mice exhibited significantly reduced contractility relative to WT controls. This impairment may result from the inflammatory stress experienced by the cardiomyocytes and suggest that dysregulation of contractility and Ca2+ reuptake in cardiomyocytes contributes to cardiac dysfunction at the whole organ level in hypereosinophilic mice.

Interleukin‐5 alleviates cardiac remodelling via the STAT3 pathway in angiotensin II‐infused mice

“…Previous studies have found that IL‐5 can regulate cardiac remodelling, such as improving cardiac remodelling after myocardial infarction and exacerbating cardiac remodelling induced by hypereosinophilia 33,34 . However, the regulatory role of IL‐5 in Ang II‐induced cardiac remodelling has not been reported.…”

“…15,[30][31][32] Considering that STATs are the most Previous studies have found that IL-5 can regulate cardiac remodelling, such as improving cardiac remodelling after myocardial infarction and exacerbating cardiac remodelling induced by hypereosinophilia. 33,34 However, the regulatory role of IL-5…”

Pathophysiology of hypereosinophilia-associated heart disease

“…The D2 model is limited in that it lacks the endocardial thrombosis, fibrosis, and systemic aspects typical of HES; furthermore, this model develops very early and resolves on its own by ~3 months of age 30 . Diny et al have shown that IL-5 transgenic mice develop worsening left ventricular function with age; however, no thrombosis or fibrosis was seen 28 . Studies in myosin-challenged IL-5 transgenic mice developed severe inflammation, followed by dilated cardiomyopathy and fibrosis 12 .…”

“…As the NIH Taskforce on Research needs of Eosinophil-Associated Diseases (TREAD) and recent RE-TREAD reported, there is a paucity of preclinical models that adequately replicate cardiac disease in hypereosinophilia, and development of these models would enable mechanistic studies aiming to develop targeted therapies 8,9 . Attempts to model hypereosinophilia-associated heart disease in mice include spontaneous eosinophilic myocarditis in DBA/2 (D2) mice 27 , baseline heart disease in aging IL-5 transgenic mice 28 , and a model of antigen (cardiac myosin)-induced autoimmune EM elicited in IL-5 transgenic mice 12,29 . The D2 model is limited in that it lacks the endocardial thrombosis, fibrosis, and systemic aspects typical of HES; furthermore, this model develops very early and resolves on its own by ~3 months of age 30 .…”