IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe–/– mice
Jing Wang, … , Peter Libby, Guo-Ping Shi
Jing Wang, … , Peter Libby, Guo-Ping Shi
Published September 1, 2011; First published August 8, 2011
Citation Information: J Clin Invest. 2011;121(9):3564-3577. https://doi.org/10.1172/JCI46028.
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Research Article Cardiology

IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe–/– mice

Abstract

IgE has a key role in the pathogenesis of allergic responses through its ability to activate mast cells via the receptor FcεR1. In addition to mast cells, many cell types implicated in atherogenesis express FcεR1, but whether IgE has a role in this disease has not been determined. Here, we demonstrate that serum IgE levels are elevated in patients with myocardial infarction or unstable angina pectoris. We found that IgE and the FcεR1 subunit FcεR1α were present in human atherosclerotic lesions and that they localized particularly to macrophage-rich areas. In mice, absence of FcεR1α reduced inflammation and apoptosis in atherosclerotic plaques and reduced the burden of disease. In cultured macrophages, the presence of TLR4 was required for FcεR1 activity. IgE stimulated the interaction between FcεR1 and TLR4, thereby inducing macrophage signal transduction, inflammatory molecule expression, and apoptosis. These IgE activities were reduced in the absence of FcεR1 or TLR4. Furthermore, IgE activated macrophages by enhancing Na+/H+ exchanger 1 (NHE1) activity. Inactivation of NHE1 blocked IgE-induced macrophage production of inflammatory molecules and apoptosis. Cultured human aortic SMCs (HuSMCs) and ECs also exhibited IgE-induced signal transduction, cytokine expression, and apoptosis. In human atherosclerotic lesions, SMCs and ECs colocalized with IgE and TUNEL staining. This study reveals what we believe to be several previously unrecognized IgE activities that affect arterial cell biology and likely other IgE-associated pathologies in human diseases.

Authors

Jing Wang, Xiang Cheng, Mei-Xiang Xiang, Mervi Alanne-Kinnunen, Jian-An Wang, Han Chen, Aina He, Xinghui Sun, Yan Lin, Ting-Ting Tang, Xin Tu, Sara Sjöberg, Galina K. Sukhova, Yu-Hua Liao, Daniel H. Conrad, Lunyin Yu, Toshiaki Kawakami, Petri T. Kovanen, Peter Libby, Guo-Ping Shi

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Figure 3

Mouse peritoneal macrophage IgE (SPE-7) responses.

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Mouse peritoneal macrophage IgE (SPE-7) responses. Immunoblots to detect...
Immunoblots to detect signaling molecule activation in IgE-treated macrophages at different times (50 μg/ml IgE) (A) or with different doses of IgE (15 minutes) (B). (C) Immunoblots to detect signaling molecule activation in IgE-treated macrophages from WT and Fcer1a–/– mice. (D) Macrophage lysate JPM labeling to detect active cathepsins (Cat; arrowheads) in macrophages treated without (–) or with (+) IgE for 2 days. (E) WT macrophage phospho-p65 and phospho-JNK expression after 15 minutes of treatment with IgE, heated IgE, and LPS (100 ng/ml). (F) IgE-stimulated phospho-p65 and phospho-JNK expression in macrophages from different mice. (G and H) IgE-induced Il6 and MCP-1 mRNA (RT-PCR) and media protein (ELISA) levels in macrophages from different mice. (I) Immunofluorescence TUNEL staining of IgE-induced apoptosis (3 days) in macrophages from different mice. Left panels are representative images (original magnification, ×100). (J) Immunoblots to detect TLR4 and FcεR1α in macrophage total lysates before and after IgE stimulation (15 minutes). (K) Immunoprecipitation for FcεR1α or TLR4 followed by immunoblot analysis for TLR4 or FcεR1α in macrophages treated with and without IgE (15 minutes). The same immunoprecipitation (IP) antibody was used for immunoblot (IB) to ensure equal antibody precipitation. Except where indicated, 50 μg/ml of IgE or heated IgE was used for all macrophage stimulations. Total p38, p65, or β-actin immunoblots were used for protein loading controls. Data in G–I are mean ± SEM of 6–10 experiments. Asterisks indicate statistically significant differences; Mann-Whitney U test.