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

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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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 macrophagerich 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.

Original languageEnglish (US)
Pages (from-to)3564-3577
Number of pages14
JournalJournal of Clinical Investigation
Volume121
Issue number9
DOIs
StatePublished - Sep 1 2011

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ASJC Scopus subject areas

  • Medicine(all)

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Wang, J., Cheng, X., Xiang, M. X., Alanne-Kinnunen, M., Wang, J. A., Chen, H., He, A., Sun, X., Lin, Y., Tang, T. T., Tu, X., Sjöberg, S., Sukhova, G. K., Liao, Y. H., Conrad, D. H., Yu, L., Kawakami, T., Kovanen, P. T., Libby, P., & Shi, G. P. (2011). IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe-/- mice. Journal of Clinical Investigation, 121(9), 3564-3577. https://doi.org/10.1172/JCI46028