{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T19:11:18Z","timestamp":1768072278108,"version":"3.49.0"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T00:00:00Z","timestamp":1645660800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Heme oxygenase-1 (HO-1) has been reported to protect against oxidation and inflammation in atherosclerosis. It remains unclear how the immune system participates in the cytoprotective function of HO-1 in the context of atherosclerosis. In this study, we attempted to investigate the potential effect of a HO-1 inducer, hemin, and a HO-1 inhibitor, Tin-protoporphyrin IX (SnPP), on the progression of atherosclerosis in ApoE deficient mice. Using mass cytometry, 15 immune cell populations and 29\u00a0T cell sub-clusters in spleen and peripheral blood were thoroughly analyzed after hemin or SnPP treatment. SnPP elevated risk factors of atherosclerosis, whereas hemin reduced them. In-depth analysis showed that hemin significantly modified the immune system in both spleen and peripheral blood. Hemin increased dendritic (DC) and myeloid-derived suppressor cells (MDSCs), but decreased natural killer (NK) cells. An opposite effect was observed with SnPP treatment in terms of NK cells. NK cells and MDSCs were positively and negatively correlated with total cholesterol and low-density lipoprotein, respectively. Moreover, the T cell profiles were significantly reshaped by hemin, whereas only minor changes were observed with SnPP. Several hemin-modulated T cell clusters associated with atherosclerosis were also identified. In summary, we have unraveled an important regulatory role for HO-1 pathway in immune cell regulation and atherosclerosis. Our finding suggests that modulating HO-1 signaling represents a potential therapeutic strategy against atherosclerosis.<\/jats:p>","DOI":"10.3389\/fphar.2022.809469","type":"journal-article","created":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T08:46:22Z","timestamp":1645692382000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Induction of Heme Oxygenase-1 Modifies the Systemic Immunity and Reduces Atherosclerotic Lesion Development in ApoE Deficient Mice"],"prefix":"10.3389","volume":"13","author":[{"given":"Leyi","family":"Yao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yali","family":"Hao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guanmei","family":"Wen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingzhong","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Penglong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinbao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1186\/s12915-020-00924-y","article-title":"Analysis of Urinary Exosomal Metabolites Identifies Cardiovascular Risk Signatures with Added Value to Urine Analysis","volume":"18","author":"Agudiez","year":"2020","journal-title":"BMC Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"6813","DOI":"10.1021\/ac901049w","article-title":"Mass Cytometry: Technique for Real Time Single Cell Multitarget Immunoassay Based on Inductively Coupled Plasma Time-Of-Flight Mass Spectrometry","volume":"81","author":"Bandura","year":"2009","journal-title":"Anal. Chem."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1089\/ars.2019.7970","article-title":"Heme Oxygenase-1 Upregulation: A Novel Approach in the Treatment of Cardiovascular Disease","volume":"32","author":"Bellner","year":"2020","journal-title":"Antioxid. Redox Signal."},{"key":"B4","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1126\/science.1198704","article-title":"Single-cell Mass Cytometry of Differential Immune and Drug Responses across a Human Hematopoietic Continuum","volume":"332","author":"Bendall","year":"2011","journal-title":"Science"},{"key":"B5","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1016\/j.cell.2014.04.005","article-title":"Single-cell Trajectory Detection Uncovers Progression and Regulatory Coordination in Human B Cell Development","volume":"157","author":"Bendall","year":"2014","journal-title":"Cell"},{"key":"B6","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1038\/nbt.2317","article-title":"Multiplexed Mass Cytometry Profiling of Cellular States Perturbed by Small-Molecule Regulators","volume":"30","author":"Bodenmiller","year":"2012","journal-title":"Nat. Biotechnol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"2120","DOI":"10.1016\/j.freeradbiomed.2012.03.002","article-title":"Reduced Circulating Oxidized LDL Is Associated with Hypocholesterolemia and Enhanced Thiol Status in Gilbert Syndrome","volume":"52","author":"Boon","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"12150","DOI":"10.1038\/ncomms12150","article-title":"Recommendations for Myeloid-Derived Suppressor Cell Nomenclature and Characterization Standards","volume":"7","author":"Bronte","year":"2016","journal-title":"Nat. Commun."},{"key":"B9","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/s41577-020-00491-x","article-title":"Regulation of Inflammation by the Antioxidant Haem Oxygenase 1","volume":"21","author":"Campbell","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1016\/j.immuni.2011.09.014","article-title":"Flt3 Signaling-dependent Dendritic Cells Protect against Atherosclerosis","volume":"35","author":"Choi","year":"2011","journal-title":"Immunity"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1360","DOI":"10.1093\/cvr\/cvy109","article-title":"Immune Cell Census in Murine Atherosclerosis: Cytometry by Time of Flight Illuminates Vascular Myeloid Cell Diversity","volume":"114","author":"Cole","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"349","DOI":"10.3389\/fonc.2014.00349","article-title":"Myeloid-derived Suppressor Cells as Therapeutic Target in Hematological Malignancies","volume":"4","author":"De Veirman","year":"2014","journal-title":"Front. Oncol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"2034","DOI":"10.1111\/j.1600-6143.2009.02757.x","article-title":"Endotoxin-induced Myeloid-Derived Suppressor Cells Inhibit Alloimmune Responses via Heme Oxygenase-1","volume":"9","author":"De Wilde","year":"2009","journal-title":"Am. J. Transpl."},{"key":"B14","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.phrs.2016.12.032","article-title":"Advanced Atherosclerosis Is Associated with Inflammation, Vascular Dysfunction and Oxidative Stress, but Not Hypertension","volume":"116","author":"Dinh","year":"2017","journal-title":"Pharmacol. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2372","DOI":"10.2741\/3860","article-title":"Protective Role of Heme Oxygenase-1 against Inflammation in Atherosclerosis","volume":"16","author":"Durante","year":"2011","journal-title":"Front. Biosci. (Landmark Ed."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.4049\/jimmunol.1601520","article-title":"Efferocytosis Signaling in the Regulation of Macrophage Inflammatory Responses","volume":"198","author":"Elliott","year":"2017","journal-title":"J. Immunol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1576","DOI":"10.1038\/s41591-019-0590-4","article-title":"Single-cell Immune Landscape of Human Atherosclerotic Plaques","volume":"25","author":"Fernandez","year":"2019","journal-title":"Nat. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"356","DOI":"10.3390\/cells8040356","article-title":"Activation of Nrf2\/HO-1 Pathway and Human Atherosclerotic Plaque Vulnerability:an In Vitro and In Vivo Study","volume":"8","author":"Fiorelli","year":"2019","journal-title":"Cells"},{"key":"B19","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1093\/cvr\/cvw114","article-title":"CD11b+Gr-1+ Myeloid-Derived Suppressor Cells Reduce Atherosclerotic Lesion Development in LDLr Deficient Mice","volume":"111","author":"Foks","year":"2016","journal-title":"Cardiovasc. Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1038\/nri2506","article-title":"Myeloid-derived Suppressor Cells as Regulators of the Immune System","volume":"9","author":"Gabrilovich","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/j.cjca.2016.12.010","article-title":"Macrophage Apoptosis and Necrotic Core Development in Atherosclerosis: A Rapidly Advancing Field with Clinical Relevance to Imaging and Therapy","volume":"33","author":"Gonzalez","year":"2017","journal-title":"Can. J. Cardiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"5293","DOI":"10.3390\/ijms20215293","article-title":"Immunobiology of Atherosclerosis: A Complex Net of Interactions","volume":"20","author":"Herrero-Fernandez","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1172\/JCI119634","article-title":"Induction of Heme Oxygenase-1 Inhibits the Monocyte Transmigration Induced by Mildly Oxidized LDL","volume":"100","author":"Ishikawa","year":"1997","journal-title":"J. Clin. Invest."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1831","DOI":"10.1161\/hc3901.095897","article-title":"Heme Oxygenase-1 Inhibits Atherogenesis in Watanabe Heritable Hyperlipidemic Rabbits","volume":"104","author":"Ishikawa","year":"","journal-title":"Circulation"},{"key":"B25","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1161\/01.res.88.5.506","article-title":"Heme Oxygenase-1 Inhibits Atherosclerotic Lesion Formation in Ldl-Receptor Knockout Mice","volume":"88","author":"Ishikawa","year":"","journal-title":"Circ. Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2073","DOI":"10.1084\/jem.20060245","article-title":"Low-grade Chronic Inflammation in Regions of the normal Mouse Arterial Intima Predisposed to Atherosclerosis","volume":"203","author":"Jongstra-Bilen","year":"2006","journal-title":"J. Exp. Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1161\/hc3801.095663","article-title":"Adenovirus-mediated Heme Oxygenase-1 Gene Transfer Inhibits the Development of Atherosclerosis in Apolipoprotein E-Deficient Mice","volume":"104","author":"Juan","year":"2001","journal-title":"Circulation"},{"key":"B28","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1097\/00041433-200404000-00018","article-title":"Inflammation, Oxidative Stress, and Atherosclerosis","volume":"15","author":"Le","year":"2004","journal-title":"Curr. Opin. Lipidol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1186\/s13075-019-1876-0","article-title":"Baicalein Ameliorates Pristane-Induced Lupus Nephritis via Activating Nrf2\/HO-1 in Myeloid-Derived Suppressor Cells","volume":"21","author":"Li","year":"2019","journal-title":"Arthritis Res. Ther."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1161\/hc0902.104353","article-title":"Inflammation and Atherosclerosis","volume":"105","author":"Libby","year":"2002","journal-title":"Circulation"},{"key":"B31","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1161\/ATVBAHA.107.158675","article-title":"CX3CR1 Deficiency Impairs Dendritic Cell Accumulation in Arterial Intima and Reduces Atherosclerotic burden","volume":"28","author":"Liu","year":"2008","journal-title":"Arterioscler Thromb. Vasc. Biol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1186\/s12967-016-0901-1","article-title":"The Apoe(-\/-) Mouse Model: a Suitable Model to Study Cardiovascular and Respiratory Diseases in the Context of Cigarette Smoke Exposure and Harm Reduction","volume":"14","author":"Lo Sasso","year":"2016","journal-title":"J. Transl. Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1254\/jphs.fp0060270","article-title":"Hemin Modulates Cytokine Expressions in Macrophage-Derived Foam Cells via Heme Oxygenase-1 Induction","volume":"103","author":"Ma","year":"2007","journal-title":"J. Pharmacol. Sci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1007\/s00395-011-0192-x","article-title":"Necrotic Cell Death in Atherosclerosis","volume":"106","author":"Martinet","year":"2011","journal-title":"Basic Res. Cardiol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"e1149","DOI":"10.1002\/cti2.1149","article-title":"Mass Cytometry Reveals Immune Signatures Associated with Cytomegalovirus (CMV) Control in Recipients of Allogeneic Haemopoietic Stem Cell Transplant and CMV-specific T Cells","volume":"9","author":"McGuire","year":"2020","journal-title":"Clin. Transl. Immunol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1007\/s13353-013-0134-4","article-title":"Mouse Models of Atherosclerosis: Explaining Critical Roles of Lipid Metabolism and Inflammation","volume":"54","author":"Mukhopadhyay","year":"2013","journal-title":"J. Appl. Genet."},{"key":"B37","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1189\/jlb.0311119","article-title":"Histone Deacetylase Inhibition Facilitates GM-CSF-Mediated Expansion of Myeloid-Derived Suppressor Cells In Vitro and In Vivo","volume":"91","author":"Rosborough","year":"2012","journal-title":"J. Leukoc. Biol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"515","DOI":"10.3390\/cells10030515","article-title":"Heme Oxgenase-1, a Cardinal Modulator of Regulated Cell Death and Inflammation","volume":"10","author":"Ryter","year":"2021","journal-title":"Cells"},{"key":"B39","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1093\/cvr\/cvu016","article-title":"Natural Killer (NK) Cells Augment Atherosclerosis by Cytotoxic-dependent Mechanisms","volume":"102","author":"Selathurai","year":"2014","journal-title":"Cardiovasc. Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1254\/jphs.sc0040188","article-title":"Induction of Heme Oxygenase-1 Inhibits Monocyte Chemoattractant Protein-1 mRNA Expression in U937 Cells","volume":"100","author":"Shokawa","year":"2006","journal-title":"J. Pharmacol. Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1126\/science.3029864","article-title":"Bilirubin Is an Antioxidant of Possible Physiological Importance","volume":"235","author":"Stocker","year":"1987","journal-title":"Science"},{"key":"B42","doi-asserted-by":"publisher","first-page":"e1112","DOI":"10.1002\/cti2.1112","article-title":"Natural Killer Cell Activation by Respiratory Syncytial Virus-specific Antibodies Is Decreased in Infants with Severe Respiratory Infections and Correlates with Fc-Glycosylation","volume":"9","author":"van Erp","year":"2020","journal-title":"Clin. Transl. Immunol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"101419","DOI":"10.1016\/j.trim.2021.101419","article-title":"Heme Oxygenase-1: Equally Important in Allogeneic Hematopoietic Stem Cell Transplantation and Organ Transplantation","volume":"68","author":"Verheij","year":"2021","journal-title":"Transpl. Immunol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1161\/CIRCRESAHA.114.302153","article-title":"Macrophage Mitochondrial Oxidative Stress Promotes Atherosclerosis and Nuclear Factor-\u039ab-Mediated Inflammation in Macrophages","volume":"114","author":"Wang","year":"2014","journal-title":"Circ. Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1002\/path.4712","article-title":"Multiple Myeloma Exosomes Establish a Favourable Bone Marrow Microenvironment with Enhanced Angiogenesis and Immunosuppression","volume":"239","author":"Wang","year":"2016","journal-title":"J. Pathol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"120152","DOI":"10.1016\/j.biomaterials.2020.120152","article-title":"Loading of Metal Isotope-Containing Intercalators for Mass Cytometry-Based High-Throughput Quantitation of Exosome Uptake at the Single-Cell Level","volume":"255","author":"Wang","year":"","journal-title":"Biomaterials"},{"key":"B47","doi-asserted-by":"publisher","first-page":"e01132","DOI":"10.1002\/cti2.1132","article-title":"Identification of the Immune Checkpoint Signature of Multiple Myeloma Using Mass Cytometry-Based Single-Cell Analysis","volume":"9","author":"Wang","year":"","journal-title":"Clin. Transl. Immunol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1161\/01.ATV.0000124923.95545.2c","article-title":"Depletion of Natural Killer Cell Function Decreases Atherosclerosis in Low-Density Lipoprotein Receptor Null Mice","volume":"24","author":"Whitman","year":"2004","journal-title":"Arterioscler Thromb. Vasc. Biol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1675","DOI":"10.1161\/CIRCRESAHA.117.312513","article-title":"Atlas of the Immune Cell Repertoire in Mouse Atherosclerosis Defined by Single-Cell RNA-Sequencing and Mass Cytometry","volume":"122","author":"Winkels","year":"2018","journal-title":"Circ. Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.1084\/jem.20052321","article-title":"Antioxidants Protect from Atherosclerosis by a Heme Oxygenase-1 Pathway that Is Independent of Free Radical Scavenging","volume":"203","author":"Wu","year":"2006","journal-title":"J. Exp. Med."},{"key":"B51","doi-asserted-by":"publisher","first-page":"23591","DOI":"10.1074\/jbc.M111.237123","article-title":"Gr-1+ CD11b+ Myeloid-Derived Suppressor Cells Suppress Inflammation and Promote Insulin Sensitivity in Obesity","volume":"286","author":"Xia","year":"2011","journal-title":"J. Biol. Chem."},{"key":"B52","doi-asserted-by":"publisher","first-page":"e1250","DOI":"10.1002\/cti2.1250","article-title":"Natural Killer Cells in Inflammatory Autoimmune Diseases","volume":"10","author":"Yang","year":"2021","journal-title":"Clin. Transl. Immunol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"e1139","DOI":"10.1002\/cti2.1139","article-title":"Plasmacytoid Dendritic Cell Biology and its Role in Immune-Mediated Diseases","volume":"9","author":"Ye","year":"2020","journal-title":"Clin. Transl. Immunol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1759","DOI":"10.1096\/fj.03-0187fje","article-title":"Absence of Heme Oxygenase-1 Exacerbates Atherosclerotic Lesion Formation and Vascular Remodeling","volume":"17","author":"Yet","year":"2003","journal-title":"FASEB J."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.809469\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T08:46:25Z","timestamp":1645692385000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.809469\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,24]]},"references-count":54,"alternative-id":["10.3389\/fphar.2022.809469"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.809469","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,24]]},"article-number":"809469"}}