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Research LetterCardiologyVascular biology
Open Access | 
10.1172/JCI182472
Modulation of the ACOD1/itaconate pathway differentially affects atherosclerosis severity across genetic models and sexes
Lara Haase,1,2 Anouar Belkacemi,3,4 Laura Neises,2 Nicole Kiweler,2 Christine Wesely,5 Rosanna Huchzermeier,6 Maja Bozic,7 Arefeh Khakdan,7 Marta Sánchez,7 Arnaud Mary,1 Nadja Sachs,4,8 Hanna Winter,4,9 Enrico Glaab,1 Michael T. Heneka,1 Emiel P.C. van der Vorst,6,10 Michel Mittelbronn,7 Johannes Meiser,2 and Jochen G. Schneider1,7
1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
2Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
3Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
4German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim/Munich, Germany.
5Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
6Department of Internal Medicine-I, University Hospital Aachen, Aachen, Germany.
7Department of Life Science and Medicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
8Department of Vascular Surgery, and
9Institute of Molecular Vascular Medicine, TUM University Hospital, Munich, Germany.
10Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany.
Address correspondence to: Jochen G. Schneider, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, avenue du Swing, L-4362-Esch-sur-Alzette, Luxembourg. Phone: 3524666446154; Email: jochen.schneider@uni.lu.
Authorship note: LH and AB contributed equally to this work.
Find articles by Haase, L. in: PubMed | Google Scholar
1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
2Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
3Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
4German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim/Munich, Germany.
5Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
6Department of Internal Medicine-I, University Hospital Aachen, Aachen, Germany.
7Department of Life Science and Medicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
8Department of Vascular Surgery, and
9Institute of Molecular Vascular Medicine, TUM University Hospital, Munich, Germany.
10Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany.
Address correspondence to: Jochen G. Schneider, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, avenue du Swing, L-4362-Esch-sur-Alzette, Luxembourg. Phone: 3524666446154; Email: jochen.schneider@uni.lu.
Authorship note: LH and AB contributed equally to this work.
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1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
2Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
3Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
4German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim/Munich, Germany.
5Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
6Department of Internal Medicine-I, University Hospital Aachen, Aachen, Germany.
7Department of Life Science and Medicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
8Department of Vascular Surgery, and
9Institute of Molecular Vascular Medicine, TUM University Hospital, Munich, Germany.
10Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany.
Address correspondence to: Jochen G. Schneider, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, avenue du Swing, L-4362-Esch-sur-Alzette, Luxembourg. Phone: 3524666446154; Email: jochen.schneider@uni.lu.
Authorship note: LH and AB contributed equally to this work.
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1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
2Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
3Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
4German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim/Munich, Germany.
5Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
6Department of Internal Medicine-I, University Hospital Aachen, Aachen, Germany.
7Department of Life Science and Medicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
8Department of Vascular Surgery, and
9Institute of Molecular Vascular Medicine, TUM University Hospital, Munich, Germany.
10Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany.
Address correspondence to: Jochen G. Schneider, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, avenue du Swing, L-4362-Esch-sur-Alzette, Luxembourg. Phone: 3524666446154; Email: jochen.schneider@uni.lu.
Authorship note: LH and AB contributed equally to this work.
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1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
2Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
3Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
4German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim/Munich, Germany.
5Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
6Department of Internal Medicine-I, University Hospital Aachen, Aachen, Germany.
7Department of Life Science and Medicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
8Department of Vascular Surgery, and
9Institute of Molecular Vascular Medicine, TUM University Hospital, Munich, Germany.
10Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany.
Address correspondence to: Jochen G. Schneider, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, avenue du Swing, L-4362-Esch-sur-Alzette, Luxembourg. Phone: 3524666446154; Email: jochen.schneider@uni.lu.
Authorship note: LH and AB contributed equally to this work.
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1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
2Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
3Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
4German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim/Munich, Germany.
5Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
6Department of Internal Medicine-I, University Hospital Aachen, Aachen, Germany.
7Department of Life Science and Medicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
8Department of Vascular Surgery, and
9Institute of Molecular Vascular Medicine, TUM University Hospital, Munich, Germany.
10Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany.
Address correspondence to: Jochen G. Schneider, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, avenue du Swing, L-4362-Esch-sur-Alzette, Luxembourg. Phone: 3524666446154; Email: jochen.schneider@uni.lu.
Authorship note: LH and AB contributed equally to this work.
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1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
2Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
3Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
4German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim/Munich, Germany.
5Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
6Department of Internal Medicine-I, University Hospital Aachen, Aachen, Germany.
7Department of Life Science and Medicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
8Department of Vascular Surgery, and
9Institute of Molecular Vascular Medicine, TUM University Hospital, Munich, Germany.
10Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany.
Address correspondence to: Jochen G. Schneider, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, avenue du Swing, L-4362-Esch-sur-Alzette, Luxembourg. Phone: 3524666446154; Email: jochen.schneider@uni.lu.
Authorship note: LH and AB contributed equally to this work.
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1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
2Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
3Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
4German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim/Munich, Germany.
5Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
6Department of Internal Medicine-I, University Hospital Aachen, Aachen, Germany.
7Department of Life Science and Medicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
8Department of Vascular Surgery, and
9Institute of Molecular Vascular Medicine, TUM University Hospital, Munich, Germany.
10Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany.
Address correspondence to: Jochen G. Schneider, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, avenue du Swing, L-4362-Esch-sur-Alzette, Luxembourg. Phone: 3524666446154; Email: jochen.schneider@uni.lu.
Authorship note: LH and AB contributed equally to this work.
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1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
2Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
3Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
4German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim/Munich, Germany.
5Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
6Department of Internal Medicine-I, University Hospital Aachen, Aachen, Germany.
7Department of Life Science and Medicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
8Department of Vascular Surgery, and
9Institute of Molecular Vascular Medicine, TUM University Hospital, Munich, Germany.
10Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany.
Address correspondence to: Jochen G. Schneider, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, avenue du Swing, L-4362-Esch-sur-Alzette, Luxembourg. Phone: 3524666446154; Email: jochen.schneider@uni.lu.
Authorship note: LH and AB contributed equally to this work.
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1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
2Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
3Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
4German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim/Munich, Germany.
5Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
6Department of Internal Medicine-I, University Hospital Aachen, Aachen, Germany.
7Department of Life Science and Medicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
8Department of Vascular Surgery, and
9Institute of Molecular Vascular Medicine, TUM University Hospital, Munich, Germany.
10Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany.
Address correspondence to: Jochen G. Schneider, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, avenue du Swing, L-4362-Esch-sur-Alzette, Luxembourg. Phone: 3524666446154; Email: jochen.schneider@uni.lu.
Authorship note: LH and AB contributed equally to this work.
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1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
2Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
3Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
4German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim/Munich, Germany.
5Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
6Department of Internal Medicine-I, University Hospital Aachen, Aachen, Germany.
7Department of Life Science and Medicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
8Department of Vascular Surgery, and
9Institute of Molecular Vascular Medicine, TUM University Hospital, Munich, Germany.
10Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany.
Address correspondence to: Jochen G. Schneider, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, avenue du Swing, L-4362-Esch-sur-Alzette, Luxembourg. Phone: 3524666446154; Email: jochen.schneider@uni.lu.
Authorship note: LH and AB contributed equally to this work.
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1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
2Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
3Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
4German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim/Munich, Germany.
5Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
6Department of Internal Medicine-I, University Hospital Aachen, Aachen, Germany.
7Department of Life Science and Medicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
8Department of Vascular Surgery, and
9Institute of Molecular Vascular Medicine, TUM University Hospital, Munich, Germany.
10Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany.
Address correspondence to: Jochen G. Schneider, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, avenue du Swing, L-4362-Esch-sur-Alzette, Luxembourg. Phone: 3524666446154; Email: jochen.schneider@uni.lu.
Authorship note: LH and AB contributed equally to this work.
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1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
2Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
3Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
4German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim/Munich, Germany.
5Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
6Department of Internal Medicine-I, University Hospital Aachen, Aachen, Germany.
7Department of Life Science and Medicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
8Department of Vascular Surgery, and
9Institute of Molecular Vascular Medicine, TUM University Hospital, Munich, Germany.
10Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany.
Address correspondence to: Jochen G. Schneider, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, avenue du Swing, L-4362-Esch-sur-Alzette, Luxembourg. Phone: 3524666446154; Email: jochen.schneider@uni.lu.
Authorship note: LH and AB contributed equally to this work.
Find articles by Glaab, E. in: PubMed | Google Scholar
1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
2Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
3Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
4German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim/Munich, Germany.
5Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
6Department of Internal Medicine-I, University Hospital Aachen, Aachen, Germany.
7Department of Life Science and Medicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
8Department of Vascular Surgery, and
9Institute of Molecular Vascular Medicine, TUM University Hospital, Munich, Germany.
10Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany.
Address correspondence to: Jochen G. Schneider, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, avenue du Swing, L-4362-Esch-sur-Alzette, Luxembourg. Phone: 3524666446154; Email: jochen.schneider@uni.lu.
Authorship note: LH and AB contributed equally to this work.
Find articles by Heneka, M. in: PubMed | Google Scholar
1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
2Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
3Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
4German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim/Munich, Germany.
5Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
6Department of Internal Medicine-I, University Hospital Aachen, Aachen, Germany.
7Department of Life Science and Medicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
8Department of Vascular Surgery, and
9Institute of Molecular Vascular Medicine, TUM University Hospital, Munich, Germany.
10Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany.
Address correspondence to: Jochen G. Schneider, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, avenue du Swing, L-4362-Esch-sur-Alzette, Luxembourg. Phone: 3524666446154; Email: jochen.schneider@uni.lu.
Authorship note: LH and AB contributed equally to this work.
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1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
2Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
3Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
4German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim/Munich, Germany.
5Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
6Department of Internal Medicine-I, University Hospital Aachen, Aachen, Germany.
7Department of Life Science and Medicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
8Department of Vascular Surgery, and
9Institute of Molecular Vascular Medicine, TUM University Hospital, Munich, Germany.
10Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany.
Address correspondence to: Jochen G. Schneider, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, avenue du Swing, L-4362-Esch-sur-Alzette, Luxembourg. Phone: 3524666446154; Email: jochen.schneider@uni.lu.
Authorship note: LH and AB contributed equally to this work.
Find articles by Mittelbronn, M. in: PubMed | Google Scholar
1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
2Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
3Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
4German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim/Munich, Germany.
5Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
6Department of Internal Medicine-I, University Hospital Aachen, Aachen, Germany.
7Department of Life Science and Medicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
8Department of Vascular Surgery, and
9Institute of Molecular Vascular Medicine, TUM University Hospital, Munich, Germany.
10Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany.
Address correspondence to: Jochen G. Schneider, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, avenue du Swing, L-4362-Esch-sur-Alzette, Luxembourg. Phone: 3524666446154; Email: jochen.schneider@uni.lu.
Authorship note: LH and AB contributed equally to this work.
Find articles by Meiser, J. in: PubMed | Google Scholar
1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
2Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
3Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
4German Centre for Cardiovascular Research (DZHK), Heidelberg/Mannheim/Munich, Germany.
5Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
6Department of Internal Medicine-I, University Hospital Aachen, Aachen, Germany.
7Department of Life Science and Medicine, University of Luxembourg, Campus Belval, Esch-sur-Alzette, Luxembourg.
8Department of Vascular Surgery, and
9Institute of Molecular Vascular Medicine, TUM University Hospital, Munich, Germany.
10Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany.
Address correspondence to: Jochen G. Schneider, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, avenue du Swing, L-4362-Esch-sur-Alzette, Luxembourg. Phone: 3524666446154; Email: jochen.schneider@uni.lu.
Authorship note: LH and AB contributed equally to this work.
Find articles by Schneider, J. in: PubMed | Google Scholar
Published June 12, 2025 - More info
J Clin Invest. 2025;135(15):e182472. https://doi.org/10.1172/JCI182472.
© 2025 Haase et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Related article:
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
To the Editor: Itaconate is a macrophage-derived metabolite central to immunometabolism (1, 2). Its role, including 4-octyl-itaconate (4-OI), has sparked interest in atherosclerosis because of its known inflammatory characteristics. Song et al. reported that 4-OI inhibits atherosclerosis in male mice in a nuclear factor erythroid 2–related factor 2–dependent (Nrf2-dependent) manner using an adeno-associated virus atherosclerosis model, while cis-aconitate decarboxylase (Acod1) knockdown, which reduces endogenous itaconate, aggravates atherosclerosis. The study suggests that “activation of the itaconate pathway may represent an important approach to treat atherosclerosis,” supporting the idea that 4-OI may have therapeutic potential (3). However, chemical differences from endogenous itaconate limit the relevance of 4-OI for modeling itaconate biology (2).
We assessed Acod1 deficiency in Ldlr–/– and Apoe–/– mouse models of athersclerosis. In Ldlr–/– Acod1–/– mice (male and female), plaque size in the aortic root and thoracic and abdominal aorta matched control plaque size (Figure 1, A–E). Similar findings were identified in Apoe–/– mice, except female Apoe–/– Acod1–/– mice showed reduced aortic arch plaque size (Supplemental Figure 1, A–E; supplemental material available online with this article; https://doi.org/10.1172/JCI182472DS1). Pooling sexes revealed reduced plaque size in Apoe–/– Acod1–/– mice in the aortic arch (P = 0.0043) and thoracic and abdominal aorta (P = 0.0218), but not on the Ldlr–/– background.
Figure 1Acod1 deletion has no effect on atherosclerosis but shows sex-dependent cholesterol metabolism in the Ldlr model. Ldlr–/–Acod1–/– and control Ldlr–/– mice (6–12 weeks old) were fed a Western diet (Envigo, TD-88137) for 12 weeks. Plaque area was measured in the aortic root (A, n = 7–8/sex/group), thoracic/abdominal aorta (C, males n = 9–16, females n = 12–14), and aortic arch (D, n = 7–8/sex/group). Representative aortic arch images from females are shown (B and E). Circulating T cells were analyzed by flow cytometry (F, males n = 10–16, females n = 12–14, pooled right), gated as CD45+TCRβ+CD19– cells. Shown are representative dot plots (G). Weight gain (H, males n = 11–16, females n = 14–15), plasma cholesterol (I, n = 8–11/group), and liver IL-1β levels (J, n = 8–10/group, pooled right) were quantified. Data are shown as mean ± SD. *P < 0.05; ***P < 0.001 by Mann-Whitney U test (A, C, and D) or Welch’s t test (F–J). Scale bars: 300 μm (B) and 1 mm (E).
Lesional foam cell area and collagen accumulation did not differ between genotypes in the Apoe–/– mouse model (Supplemental Figure 1, F and G), and heart weight was also comparable between genotypes in both mouse models (Supplemental Figure 1, H and I). These results align with Harber et al., who found more stable plaques in Ldlr–/– female mice transplanted with male Acod1–/– bone marrow (4).
Cholesterol influx and efflux in bone marrow–derived macrophages from Ldlr–/– Acod1–/– and Apoe–/– Acod1–/– mice were unchanged (Supplemental Figure 2, A–C). Itaconate is known to affect cytokines (1, 2). Unlike the observation made by Song et al. (3), we found no difference in plasma cytokines in atherosclerotic male mice (Supplemental Figure 2D). However, we identified a significant increase in the proportion of circulating T cells in female Apoe–/– Acod1–/– mice, which was not observed in Ldlr–/– Acod1–/– mice (Figure 1, F and G, and Supplemental Figure 2E).
Male Ldlr–/– Acod1–/– mice gained significantly more weight and had elevated plasma cholesterol (Figure 1, H and I), suggesting a metabolic shift in Ldlr–/– mice (5). Yet, hepatic cholesterol and triglyceride content did not differ between Ldlr–/–Acod1–/– and control mice (Supplemental Figure 2, H and I). Liver IL-1β increased in pooled samples but did not differ when compared by sex (Figure 1J and Supplemental Figure 2J). Body weight and plasma cholesterol did not differ between Apoe–/– Acod1–/– and control mice (Supplemental Figure 2, F and G).
Glucose tolerance tests after 4 weeks of Western diet feeding revealed no difference in Ldlr–/– Acod1–/– mice versus controls (Supplemental Figure 3, A and B). Consistent with these findings, hepatic and adipose p-AKT/AKT ratios were similar between genotypes (Supplemental Figure 3, C–F). There was a slight trend toward lower IRS-2–dependent PI3K activity in male Ldlr–/– Acod1–/– mice. The expression level of Cpt1a, Cpt2, Acox1, Acox2, Acly, Srebf1, Ppara, Pparg, and Acat2 was not different between both genotypes (Supplemental Figure 3, G–I).
Cyr et al. (6) recently reported a protective role for itaconate in mice, employing the same disease model but different Western diet and bone marrow transplantation. However, their experiments included male and female mice, pooling results and not assessing sex-specific differences in atherosclerosis. While we observe similar differences when pooling all mice by sex, these effects vanish when data are analyzed separately by sex (Figure 1, A–E). Consistent with Song et al., Cyr et al. also reported ACOD1 upregulation in human coronary atherosclerotic lesions, suggesting a protective role for itaconate.
RNA-seq and single-cell RNA-seq (scRNA-seq) data revealed low ACOD1 expression in human carotid plaques, in contrast with established atherosclerosis markers. In scRNA-seq data from early and advanced human carotid lesions, ACOD1 was detected in only approximately 0.75%–1% of resident macrophages from male individuals and low expression was confirmed in macrophages from asymptomatic females (Supplemental Figure 4, A–G), suggesting sex- and symptom-related differences. Nevertheless, immunohistochemistry confirmed ACOD1 expression associated with inflammatory cells of plaques from both sexes (Supplemental Figure 4H). Although these findings confirm the presence of ACOD1 in atherosclerotic lesions, low expression levels likely contribute to the variability of the data.
In conclusion, modulation of the ACOD1/itaconate pathway varies by the model used and the sex of the species. The relevance of ACOD1 in human atherosclerosis warrants further studies.
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