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 7

IgE effects on HuECs and HuSMCs.

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IgE effects on HuECs and HuSMCs. (A) IgE and TUNEL reactivity in adventi...
(A) IgE and TUNEL reactivity in adventitial microvessels (V, left 2 panels) and TUNEL activity in luminal ECs and fibrous cap SMCs (right 2 panels, corresponding to Figure 1, B and C, top panels) in human atherosclerotic lesions. Original magnifications, ×100, insets: ×400. (B) Phospho-p38 and phospho-JNK immunoblots in HuECs stimulated with IgE (15 minutes). (C) Cleaved caspase-3 (Casp-3) immunoblot in HuECs treated without (–) and with (+) IgE. (D) HuEC cell death induced with different concentrations of human IgE. (E) IgE-induced cell death of different numbers of HuECs. (F) Phospho-p38 and phospho-JNK immunoblots in HuSMCs after IgE stimulation at different time points. (G) BAX expression in HuSMCs treated with or without IgE. (H) HuSMC cell death after IgE treatment. Representative images are shown. Original magnification, ×40. (I) HuSMC cell death after treatment with different concentrations of IgE. (J) Phospho-p65 and phospho-ERK1/2 immunoblots in HuSMCs, treated with or without IgE for different times. (K) Culture medium IFN-γ, TNF-α, and IL-6 in HuSMCs, treated with or without IgE for 2 days. (L) Cathepsin JPM labeling of HuSMCs before and after IgE stimulation. Arrowheads indicate different active cathepsins. Except where indicated, 100 μg/ml human IgE was used for all HuEC and HuSMC experiments. Data in D, E, H, I, and K are mean ± SEM from approximately 6–10 experiments. Cell death data in D, H, and I were from MTT assays, and CyQUANT cell proliferation assay was used for E. Asterisks indicate statistically significant differences; Mann-Whitney U test.