Itaconate suppresses atherosclerosis by activating a Nrf2-dependent antiinflammatory response in macrophages in mice
Jianrui Song, Yanling Zhang, Ryan A. Frieler, Anthony Andren, Sherri Wood, Daniel J. Tyrrell, Peter Sajjakulnukit, Jane C. Deng, Costas A. Lyssiotis, Richard M. Mortensen, Morgan Salmon, Daniel R. Goldstein
Jianrui Song, Yanling Zhang, Ryan A. Frieler, Anthony Andren, Sherri Wood, Daniel J. Tyrrell, Peter Sajjakulnukit, Jane C. Deng, Costas A. Lyssiotis, Richard M. Mortensen, Morgan Salmon, Daniel R. Goldstein
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Research Article Cardiology Inflammation

Itaconate suppresses atherosclerosis by activating a Nrf2-dependent antiinflammatory response in macrophages in mice

Abstract

Itaconate has emerged as a critical immunoregulatory metabolite. Here, we examined the therapeutic potential of itaconate in atherosclerosis. We found that both itaconate and the enzyme that synthesizes it, aconitate decarboxylase 1 (Acod1, also known as immune-responsive gene 1 [IRG1]), are upregulated during atherogenesis in mice. Deletion of Acod1 in myeloid cells exacerbated inflammation and atherosclerosis in vivo and resulted in an elevated frequency of a specific subset of M1-polarized proinflammatory macrophages in the atherosclerotic aorta. Importantly, Acod1 levels were inversely correlated with clinical occlusion in atherosclerotic human aorta specimens. Treating mice with the itaconate derivative 4-octyl itaconate attenuated inflammation and atherosclerosis induced by high cholesterol. Mechanistically, we found that the antioxidant transcription factor, nuclear factor erythroid 2–related factor 2 (Nrf2), was required for itaconate to suppress macrophage activation induced by oxidized lipids in vitro and to decrease atherosclerotic lesion areas in vivo. Overall, our work shows that itaconate suppresses atherogenesis by inducing Nrf2-dependent inhibition of proinflammatory responses in macrophages. Activation of the itaconate pathway may represent an important approach to treat atherosclerosis.

Authors

Jianrui Song, Yanling Zhang, Ryan A. Frieler, Anthony Andren, Sherri Wood, Daniel J. Tyrrell, Peter Sajjakulnukit, Jane C. Deng, Costas A. Lyssiotis, Richard M. Mortensen, Morgan Salmon, Daniel R. Goldstein

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Figure 1

Acod1 expression and Itaconate production increase in atherosclerotic aorta.

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Acod1 expression and Itaconate production increase in atherosclerotic ao...
Atherosclerosis was induced by intraperitoneally injecting mice with PCSK9-AAV and feeding a Western diet (WD) for 10 weeks. (A) Acod1 mRNA levels in control (Con, n = 8) and atherosclerotic (Athero, n = 7) aortas were measured by qRT-PCR. (B) Aorta lysates from Con and Athero mice were separated by gel electrophoresis and proteins were detected by Western blotting with the indicated antibodies. The quantification of Acod1 (n = 9/group) after normalization to GAPDH is shown on the right. (C) Relative abundance of TCA cycle metabolites (itaconate, isocitrate, α-ketoglutarate, succinate, malate, pyruvate, citrate, and cis-aconitate) was measured by metabolomics in nonatherosclerotic control (n = 12) and atherosclerotic (n = 7) aortas. a.u., arbitrary units based on MS peak area. The absolute concentrations of itaconate in aortas were also measured. (D) Representative images of anti-Acod1–stained human atherosclerotic coronary artery. Correlation between the percentage Acod1-positive area and clinical occlusion using 2-sided Pearson’s correlation analysis is shown on the right (n = 22). In A–C, results are presented as mean ± SEM, and unpaired, 2-tailed Student’s t test was used for statistical analysis.