Role of IgE-FcεR1 in Pathological Cardiac Remodeling and Dysfunction.
Role of IgE-FcεR1 in Pathological Cardiac Remodeling and Dysfunction.
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Ig E-FcεR1在病理性心脏重构和功能障碍中的作用
DOI：
10.1161/circulationaha.120.047852
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发表时间：
2020-11
期刊：
影响因子：
37.8
通讯作者：
Hongmei Zhao;Hongqin Yang;Chi Geng;Yang Chen;J. Pang;T. Shu;Meijun Zhao;Yaqin Tang;Zhiwei Li;Baicun Li;Cui-liu Hou;Xiaomin Song;A. Wu;Xiaoxiao Guo;Si Chen;B. Liu;C. Yan;Jing Wang
中科院分区：
文献类型：
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作者：
Hongmei Zhao;Hongqin Yang;Chi Geng;Yang Chen;J. Pang;T. Shu;Meijun Zhao;Yaqin Tang;Zhiwei Li;Baicun Li;Cui-liu Hou;Xiaomin Song;A. Wu;Xiaoxiao Guo;Si Chen;B. Liu;C. Yan;Jing Wang
背景：免疫球蛋白E（IgE）是一类参与特异性过敏原免疫应答的免疫球蛋白。然而，IgE和IgE受体（FcεR1）在病理性心脏重构和心力衰竭（HF）中的作用尚不清楚。方法：检测人和小鼠心肌组织中IgE水平和心肌IgE受体（FcεR1）的表达。通过体内FcεR1基因缺失、抗IgE抗体和骨髓（BM）移植，探讨了FcεR1信号传导在病理性心脏重塑中的作用。在体外原代培养的大鼠心肌细胞（CMs）和心脏成纤维细胞（CFs）中进一步研究IgE-FcεR1通路的作用。使用RNA-seq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。结果如下：HF患者血清IgE水平显着升高，以及在两个小鼠心脏疾病模型诱导的慢性压力超负荷通过横向主动脉收缩（TAC）和慢性血管紧张素II（Ang II）输注。有趣的是，FcεR1表达水平在人类和小鼠的衰竭心脏中也显著上调。通过FcεR1敲除阻断IgE-Fcε R1通路可减轻TAC或Ang II诱导的病理性心脏重塑和/或功能障碍。抗IgE抗体（包括临床药物奥马珠单抗）也显着减轻血管紧张素II诱导的心脏重塑。骨髓移植实验表明，IgE诱导的心脏重塑是通过非骨髓来源的细胞介导的。FcεR1在CM和CF中均有表达。在培养的大鼠CM中，IgE诱导的CM肥大和肥大标志物表达通过消耗FcεR1而被消除。在培养的大鼠CF中，IgE诱导的CF激活和基质蛋白产生也被FcεR1缺陷所阻断。RNA-seq和信号通路分析显示，转化生长因子-β（TGF-β）可能是一个关键的介质，阻断TGF-β确实减轻了体外IgE诱导的心肌细胞肥大和心脏成纤维细胞活化。结论：我们的研究结果表明，IgE诱导在病理性心脏重塑中起着致病作用，至少部分通过激活CM和CF中的IgE-FcεR1信号传导。靶向IgE-FcεR1轴的治疗策略可能对管理IgE介导的心脏重塑有效。
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.