State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Pathophysiology, Peking Union Medical College, Beijing (H.Z., H.Y., C.G., J.P., T.S., M.Z., Y.T., Z.L., B.L., C.H., X.S., J.W.).
Department of Pharmacology, School of Basic Medical Sciences, Inner Mongolia Medical University, Huhhot, China (Y.C.).
Circulation. 2021 Mar 9;143(10):1014-1030. doi: 10.1161/CIRCULATIONAHA.120.047852. Epub 2020 Dec 11.
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 are unknown.
Serum IgE levels and cardiac 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 transplantation. The roles of the IgE-FcεR1 pathway were further evaluated in vitro in primary cultured rat cardiomyocytes and cardiac fibroblasts (CFs). RNA sequencing and bioinformatic analyses were used to identify biochemical changes and signaling pathways that are regulated by IgE/FcεR1.
Serum IgE levels were significantly elevated in patients with heart failure as well as in 2 mouse cardiac disease models induced by chronic pressure overload via transverse aortic constriction and chronic angiotensin II infusion. Interestingly, FcεR1 expression levels were also significantly upregulated in failing hearts from human and mouse. Blockade of the IgE-FcεR1 pathway by FcεR1 knockout alleviated transverse aortic constriction- or angiotensin II-induced pathological cardiac remodeling or dysfunction. Anti-IgE antibodies (including the clinical drug omalizumab) also significantly alleviated angiotensin II-induced cardiac remodeling. Bone marrow transplantation experiments indicated that IgE-induced cardiac remodeling was mediated through non-bone marrow-derived cells. FcεR1 was found to be expressed in both cardiomyocytes and CFs. In cultured rat cardiomyocytes, IgE-induced cardiomyocyte 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 sequencing and signaling pathway analyses revealed that transforming growth factor-β may be a critical mediator, and blocking transforming growth factor-β indeed alleviated IgE-induced cardiomyocyte hypertrophy and cardiac fibroblast activation in vitro.
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 cardiomyocytes and CFs. Therapeutic strategies targeting the IgE-FcεR1 axis may be effective for managing IgE-mediated cardiac remodeling.
免疫球蛋白 E（IgE）属于一类参与针对特定过敏原的免疫反应的免疫球蛋白。然而，IgE 和 IgE 受体（FcεR1）在病理性心脏重构和心力衰竭中的作用尚不清楚。
评估了人类和小鼠患病心脏中的血清 IgE 水平和心脏 FcεR1 表达。通过 FcεR1 基因缺失、抗 IgE 抗体和骨髓移植在体内探索了 FcεR1 信号在病理性心脏重构中的作用。在原代培养的大鼠心肌细胞和心脏成纤维细胞（CFs）中进一步评估了 IgE-FcεR1 途径的作用。使用 RNA 测序和生物信息学分析来鉴定由 IgE/FcεR1 调节的生化变化和信号通路。
心力衰竭患者以及通过横主动脉缩窄和慢性血管紧张素 II 输注诱导的 2 种小鼠心脏疾病模型的血清 IgE 水平均显着升高。有趣的是，人源和鼠源衰竭心脏中的 FcεR1 表达水平也显着上调。FcεR1 缺失通过阻断 IgE-FcεR1 途径减轻了横主动脉缩窄或血管紧张素 II 诱导的病理性心脏重构或功能障碍。抗 IgE 抗体（包括临床药物奥马珠单抗）也显着减轻了血管紧张素 II 诱导的心脏重构。骨髓移植实验表明，IgE 诱导的心脏重构是通过非骨髓来源的细胞介导的。在培养的大鼠心肌细胞中，通过耗尽 FcεR1 消除了 IgE 诱导的心肌细胞肥大和肥大标志物的表达。在培养的大鼠 CFs 中，FcεR1 缺乏也阻断了 IgE 诱导的 CF 激活和基质蛋白产生。RNA 测序和信号通路分析表明，转化生长因子-β可能是一个关键介质，并且阻断转化生长因子-β实际上在体外减轻了 IgE 诱导的心肌细胞肥大和心脏成纤维细胞激活。
我们的研究结果表明，IgE 诱导在病理性心脏重构中起因果作用，至少部分通过在心肌细胞和 CFs 中激活 IgE-FcεR1 信号转导。针对 IgE-FcεR1 轴的治疗策略可能对管理 IgE 介导的心脏重构有效。
