Role of IgE-FcεR1 in Pathological Cardiac Remodeling and Dysfunction

Abstract

Background: Immunoglobulin E (IgE) belongs to a class of immunoglobulins involved in immune response to specific allergens. However, the roles of IgE and IgE receptor (FcεR1) in pathological cardiac remodeling and heart failure (HF) are unknown. Methods: Serum IgE levels and cardiac IgE receptor (FcεR1) expression were assessed in diseased hearts from human and mouse. The role of FcεR1 signaling in pathological cardiac remodeling was explored in vivo by FcεR1 genetic depletion, anti-IgE antibodies, and bone-marrow (BM) transplantation. The roles of IgE-FcεR1 pathway were further evaluated in vitro in primary cultured rat cardiomyocytes (CMs) and cardiac fibroblasts (CFs). RNA-seq and bioinformatic analyses were used to identify biochemical changes and signaling pathways that are regulated by IgE/FcεR1. Results: Serum IgE levels were significantly elevated in patients with HF as well as in two mouse cardiac disease models induced by chronic pressure overload via transverse aortic contraction (TAC) and chronic angiotensin II (Ang II) infusion. Interestingly, FcεR1 expression levels were also significantly up-regulated in failing hearts from human and mouse. Blockade of the IgE-FcεR1 pathway by FcεR1 knockout alleviated TAC- or Ang II-induced pathological cardiac remodeling and/or dysfunction. Anti-IgE antibodies (including the clinical drug, omalizumab) also significantly alleviated Ang II-induced cardiac remodeling. BM transplantation experiments indicated that IgE-induced cardiac remodeling was mediated through non-BM-derived cells. FcεR1 was found to be expressed in both CMs and CFs. In cultured rat CMs, IgE-induced CM hypertrophy and hypertrophic marker expression were abolished by depleting FcεR1. In cultured rat CFs, IgE-induced CF activation and matrix protein production were also blocked by FcεR1 deficiency. RNA-seq and signaling pathway analyses revealed that transforming growth factor-β (TGF-β) may be a critical mediator and blocking TGF-β indeed alleviated IgE-induced cardiomyocyte hypertrophy and cardiac fibroblast activation in vitro . Conclusions: Our findings suggest that IgE induction plays a causative role in pathological cardiac remodeling, at least partially via the activation of IgE-FcεR1 signaling in CMs and CFs. Therapeutic strategies targeting the IgE-FcεR1 axis may be effective for managing IgE-mediated cardiac remodeling.

Elevated IgE promotes cardiac fibrosis by suppressing miR-486a-5p

“…Mice cardiac function was evaluated by M-mode echocardiography on the short axis using a 30-MHz probe (Vevo 2100 system; Visual Sonics, Toronto, CA) 14 . The LV measurements were taken at the papillary muscle level.…”

“…Systolic and diastolic blood pressures were measured using the non-invasive tail-cuff method (CODA, Kent Scientific, USA) as described previously 14 . Briefly, mice were encouraged to walk into the restraint tubes and their tails were restrained from passing through the occlusion tail cuff.…”

“…IgE is one of five classes of immunoglobins and they mainly function in allergic reactions 6 . It has been previously reported that high IgE levels are associated with several types of cardiovascular disorders, including abdominal aortic aneurysm 7 , 8 , atherosclerosis 9 - 11 , atherosclerotic cardiovascular disease (ASCVD) 12 , 13 , and HF 14 . Our recent study revealed a crucial role for IgE and its high affinity receptor (FcεR1) in promoting myocardial interstitial fibrosis and ventricular remodeling 14 .…”

“…It has been previously reported that high IgE levels are associated with several types of cardiovascular disorders, including abdominal aortic aneurysm 7 , 8 , atherosclerosis 9 - 11 , atherosclerotic cardiovascular disease (ASCVD) 12 , 13 , and HF 14 . Our recent study revealed a crucial role for IgE and its high affinity receptor (FcεR1) in promoting myocardial interstitial fibrosis and ventricular remodeling 14 . We found that IgE could directly activate primary rat CFs and promote matrix protein production in an FcεR1-dependent manner, while identifying TGF-β as a critical mediator of this process 14 .…”

“…Our recent study revealed a crucial role for IgE and its high affinity receptor (FcεR1) in promoting myocardial interstitial fibrosis and ventricular remodeling 14 . We found that IgE could directly activate primary rat CFs and promote matrix protein production in an FcεR1-dependent manner, while identifying TGF-β as a critical mediator of this process 14 . It has become clear that microRNAs (miRNAs) also play key roles in regulating cardiac fibrosis 15 , 16 .…”