Interleukin 18 function in atherosclerosis is mediated by the interleukin 18 receptor and the Na-Cl co-transporter

Jing Wang, Chongxiu Sun, Norbert Gerdes, Conglin Liu, Mengyang Liao, Jian Liu, Michael A. Shi, Aina He, Yi Zhou, Galina K. Sukhova, Huimei Chen, Xian Wu Cheng, Masafumi Kuzuya, Toyoaki Murohara, Jie Zhang, Xiang Cheng, Mengmeng Jiang, Gary E. Shull, Shaunessy Rogers, Chao Ling YangQiang Ke, Sabina Jelen, René Bindels, David H. Ellison, Petr Jarolim, Peter Libby, Guo Ping Shi

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Interleukin-18 (IL18) participates in atherogenesis through several putative mechanisms. Interruption of IL18 action reduces atherosclerosis in mice. Here, we show that absence of the IL18 receptor (IL18r) does not affect atherosclerosis in apolipoprotein E-deficient (Apoe-/-) mice, nor does it affect IL18 cell surface binding to or signaling in endothelial cells. As identified initially by co-immunoprecipitation with IL18, we found that IL18 interacts with the Na-Cl co-transporter (NCC; also known as SLC12A3), a 12-transmembrane-domain ion transporter protein preferentially expressed in the kidney. NCC is expressed in atherosclerotic lesions, where it colocalizes with IL18r. In Apoe-/- mice, combined deficiency of IL18r and NCC, but not single deficiency of either protein, protects mice from atherosclerosis. Peritoneal macrophages from Apoe-/- mice or from Apoe-/- mice lacking IL18r or NCC show IL18 binding and induction of cell signaling and cytokine and chemokine expression, but macrophages from Apoe-/- mice with combined deficiency of IL18r and NCC have a blunted response. An interaction between NCC and IL18r on macrophages was detected by co-immunoprecipitation. IL18 binds to the cell surface of NCC-transfected COS-7 cells, which do not express IL18r, and induces cell signaling and cytokine expression. This study identifies NCC as an IL18-binding protein that collaborates with IL18r in cell signaling, inflammatory molecule expression, and experimental atherogenesis.

Original languageEnglish (US)
Pages (from-to)820-826
Number of pages7
JournalNature medicine
Volume21
Issue number7
DOIs
StatePublished - Jul 9 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Wang, J., Sun, C., Gerdes, N., Liu, C., Liao, M., Liu, J., Shi, M. A., He, A., Zhou, Y., Sukhova, G. K., Chen, H., Cheng, X. W., Kuzuya, M., Murohara, T., Zhang, J., Cheng, X., Jiang, M., Shull, G. E., Rogers, S., ... Shi, G. P. (2015). Interleukin 18 function in atherosclerosis is mediated by the interleukin 18 receptor and the Na-Cl co-transporter. Nature medicine, 21(7), 820-826. https://doi.org/10.1038/nm.3890