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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,4,9]]},"abstract":"<jats:p>\n                    Atherosclerosis is fueled by a failure to resolve lipid-driven inflammation within the vasculature that drives plaque formation. Therapeutic approaches to reverse atherosclerotic inflammation are needed to address the rising global burden of cardiovascular disease (CVD). Recently, metabolites have gained attention for their immunomodulatory properties, including itaconate, which is generated from the tricarboxylic acid-intermediate cis-aconitate by the enzyme Immune Responsive Gene 1 (IRG1\/ACOD1). Here, we tested the therapeutic potential of the IRG1\u2013itaconate axis for human atherosclerosis. Using single-cell RNA sequencing (scRNA-seq), we found that\n                    <jats:italic>IRG1<\/jats:italic>\n                    is up-regulated in human coronary atherosclerotic lesions compared to patient-matched healthy vasculature, and in mouse models of atherosclerosis, where it is primarily expressed by plaque monocytes, macrophages, and neutrophils. Global or hematopoietic\n                    <jats:italic>Irg1<\/jats:italic>\n                    -deficiency in mice increases atherosclerosis burden, plaque macrophage and lipid content, and expression of the proatherosclerotic cytokine interleukin (IL)-1\u03b2. Mechanistically, absence of\n                    <jats:italic>Irg1<\/jats:italic>\n                    increased macrophage lipid accumulation, and accelerated inflammation via increased neutrophil extracellular trap (NET) formation and NET-priming of the NLRP3-inflammasome in macrophages, resulting in increased IL-1\u03b2 release. Conversely, supplementation of the\n                    <jats:italic>Irg1<\/jats:italic>\n                    \u2013itaconate axis using 4-octyl itaconate (4-OI) beneficially remodeled advanced plaques and reduced lesional IL-1\u03b2 levels in mice. To investigate the effects of 4-OI in humans, we leveraged an ex vivo systems-immunology approach for CVD drug discovery. Using CyTOF and scRNA-seq of peripheral blood mononuclear cells treated with plasma from CVD patients, we showed that 4-OI attenuates proinflammatory phospho-signaling and mediates anti-inflammatory rewiring of macrophage populations. Our data highlight the relevance of pursuing IRG1\u2013itaconate axis supplementation as a therapeutic approach for atherosclerosis in humans.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2400675121","type":"journal-article","created":{"date-parts":[[2024,4,2]],"date-time":"2024-04-02T14:40:21Z","timestamp":1712068821000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":73,"title":["The IRG1\u2013itaconate axis protects from cholesterol-induced inflammation and atherosclerosis"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0715-4112","authenticated-orcid":false,"given":"Yannick","family":"Cyr","sequence":"first","affiliation":[{"name":"Cardiovascular Research Center, New York University Grossman School of Medicine, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5181-2274","authenticated-orcid":false,"given":"Fazli K.","family":"Bozal","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, New York University Grossman School of Medicine, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Gabriel","family":"Barcia Dur\u00e1n","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, New York University Grossman School of Medicine, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra A. 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Martin","family":"Schlegel","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care, School of Medicine and Health, Technical University of Munich, Munich 81675, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha D.","family":"Dupuis","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, New York University Grossman School of Medicine, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard F.","family":"Sanchez","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, New York University Grossman School of Medicine, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann Marie","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, New York University Grossman School of Medicine, New York, NY 10016"},{"name":"Division of Endocrinology, Diabetes and Metabolism, New York University Langone Health, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9802-143X","authenticated-orcid":false,"given":"Edward A.","family":"Fisher","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, New York University Grossman School of Medicine, New York, NY 10016"},{"name":"Department of Cell Biology, New York University Grossman School of Medicine, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5817-2003","authenticated-orcid":false,"given":"Coen","family":"van Solingen","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, New York University Grossman School of Medicine, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Giannarelli","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, New York University Grossman School of Medicine, New York, NY 10016"},{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2505-2547","authenticated-orcid":false,"given":"Kathryn J.","family":"Moore","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, New York University Grossman School of Medicine, New York, NY 10016"},{"name":"Department of Cell Biology, New York University Grossman School of Medicine, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,4,2]]},"reference":[{"key":"e_1_3_4_1_2","first-page":"2525","article-title":"Inflammation during the life cycle of the atherosclerotic plaque","volume":"117","author":"Libby P.","year":"2021","unstructured":"P. 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Cyr IMMUNE-RESPONSIVE GENE 1 REGULATES ATHEROSCLEROTIC PLAQUE INFLAMMATION. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE252243. 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