{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T01:57:21Z","timestamp":1792547841614,"version":"4.5.0"},"reference-count":59,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T00:00:00Z","timestamp":1752796800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2025,7,18]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              Atherosclerosis is characterized by immune cell accumulation in the arterial wall and adaptive CD4\n              <jats:sup>+<\/jats:sup>\n              T helper 1 immunity contributes to atherosclerosis development. However, how conventional dendritic cells (DCs) orchestrate this adaptive response remains controversial. This study unveils strategies for the gain and loss of function of cDCs to decipher their role in atherosclerosis induction in relation to adaptive T-cell immunity.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              We tested atherosclerosis in\n              <jats:italic toggle=\"yes\">Ldlr<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice fed a high-cholesterol diet (HCD). Expansion of DCs in vivo was achieved by overexpression of FLT3L (Fms-like tyrosine kinase 3 ligand), while the effect of ablation of conventional type 1 DCs (cDC1s) in atherosclerosis was analyzed by grafting bone marrow from different mouse models of cDC1 depletion, including\n              <jats:italic toggle=\"yes\">Xcr1<\/jats:italic>\n              <jats:sup>Cre\u2212DTA<\/jats:sup>\n              and\n              <jats:italic toggle=\"yes\">Irf8<\/jats:italic>\n              \u039432 mice, into lethally irradiated\n              <jats:italic toggle=\"yes\">Ldlr<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              recipients before HCD. CD3\n              <jats:sup>+<\/jats:sup>\n              T-cell subsets were analyzed using flow cytometry or single-cell RNA sequencing (scRNA-seq). Nanoparticles loaded with dexamethasone and decorated with anti-CLEC9A antibody to target cDC1s were tested for immunotherapy.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Expansion of DCs in\n              <jats:italic toggle=\"yes\">Ldlr<\/jats:italic>\n              <jats:sup>\n                \u2212\n                <jats:italic toggle=\"yes\">\/<\/jats:italic>\n                \u2212\n              <\/jats:sup>\n              mice fed HCD for 8 weeks led to increased atherosclerotic lesion, which was prevented when\n              <jats:italic toggle=\"yes\">Ldlr<\/jats:italic>\n              <jats:sup>\n                \u2212\n                <jats:italic toggle=\"yes\">\/<\/jats:italic>\n                \u2212\n              <\/jats:sup>\n              mice were grafted before DC expansion with\n              <jats:italic toggle=\"yes\">Xcr1<\/jats:italic>\n              <jats:sup>Cre\u2212DTA<\/jats:sup>\n              cDC1-depleted bone marrow compared with controls. Consistently, even in the absence of DC expansion, cDC1 deficiency prevented HCD-induced atherosclerosis. The scRNA-seq analysis of aortic CD3\n              <jats:sup>+<\/jats:sup>\n              T cells in this experimental approach showed a local reduction in CD4\n              <jats:sup>+<\/jats:sup>\n              Th1 and CD8\n              <jats:sup>+<\/jats:sup>\n              IFN (interferon)-\u03b3\n              <jats:sup>+<\/jats:sup>\n              T cells in the absence of cDC1s compared with control mice. Mechanistically, stimulator of IFN genes (STING) in cDC1s was required for the proatherogenic function of cDC1s. As a potential cDC1-targeted immunotherapy for atherosclerosis, we generated lipid nanoparticles decorated with an anti-CLEC9A antibody to specifically target cDC1s. When loaded with the immunosuppressive drug dexamethasone, these nanoparticles promoted a reduction of the atherosclerotic lesion in\n              <jats:italic toggle=\"yes\">Ldlr<\/jats:italic>\n              <jats:sup>\n                \u2212\n                <jats:italic toggle=\"yes\">\/<\/jats:italic>\n                \u2212\n              <\/jats:sup>\n              mice fed HCD, correlating with decreased CD4\n              <jats:sup>+<\/jats:sup>\n              Th1 and CD8\n              <jats:sup>+<\/jats:sup>\n              IFN-\u03b3\n              <jats:sup>+<\/jats:sup>\n              T cells in the spleen. These immunosuppressive nanoparticles, however, did not impair antiviral response.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>\n              Using state-of-the-art strategies, our results establish that cDC1s have a proatherogenic role in atherosclerosis by boosting CD4\n              <jats:sup>+<\/jats:sup>\n              and CD8\n              <jats:sup>+<\/jats:sup>\n              T-cell immunity and propose that cDC1s can be targeted with an immunosuppressive drug to decrease atherosclerosis progression.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.124.325792","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T05:00:17Z","timestamp":1748581217000},"page":"400-416","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":18,"title":["cDC1s Promote Atherosclerosis via Local Immunity and Are Targetable for Therapy"],"prefix":"10.1161","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6695-1509","authenticated-orcid":true,"given":"Miguel","family":"Gal\u00e1n","sequence":"first","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.G., V.N., M.F.-M., P.F.-B., E.M.-R., S.M.-C., E.H.-G., M.R.-T., A.R.-R., C.R.-R., A.B., A.R.R., I.R.-V., D.S.)."},{"name":"Escuela de Doctorado, Universidad Aut\u00f3noma de Madrid, Spain (M.G., E.M.-R., A.R.-R., C.R.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8783-2330","authenticated-orcid":true,"given":"Laura","family":"Fern\u00e1ndez-M\u00e9ndez","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Cooperativa en Biomateriales (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), San Sebastian, Spain (L.F.-M., S.C.-R., J.R.-C.)."},{"name":"Universidad del Pa\u00eds Vasco\/Euskal Herriko Unibertsitatea (UPV\/EHU), Donostia, Spain (L.F.-M., S.C.-R., J.R.-C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"N\u00fa\u00f1ez","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.G., V.N., M.F.-M., P.F.-B., E.M.-R., S.M.-C., E.H.-G., M.R.-T., A.R.-R., C.R.-R., A.B., A.R.R., I.R.-V., D.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9742-3242","authenticated-orcid":true,"given":"Marcos","family":"Femen\u00eda-Mui\u00f1a","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.G., V.N., M.F.-M., P.F.-B., E.M.-R., S.M.-C., E.H.-G., M.R.-T., A.R.-R., C.R.-R., A.B., A.R.R., I.R.-V., D.S.)."},{"name":"Escuela de Doctorado (M.F.-M.), Universidad Complutense de Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9367-0643","authenticated-orcid":true,"given":"Pau","family":"Figuera-Belmonte","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.G., V.N., M.F.-M., P.F.-B., E.M.-R., S.M.-C., E.H.-G., M.R.-T., A.R.-R., C.R.-R., A.B., A.R.R., I.R.-V., D.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4157-5858","authenticated-orcid":true,"given":"Elena","family":"Moya-Ruiz","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.G., V.N., M.F.-M., P.F.-B., E.M.-R., S.M.-C., E.H.-G., M.R.-T., A.R.-R., C.R.-R., A.B., A.R.R., I.R.-V., D.S.)."},{"name":"Escuela de Doctorado, Universidad Aut\u00f3noma de Madrid, Spain (M.G., E.M.-R., A.R.-R., C.R.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarai","family":"Mart\u00ednez-Cano","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.G., V.N., M.F.-M., P.F.-B., E.M.-R., S.M.-C., E.H.-G., M.R.-T., A.R.-R., C.R.-R., A.B., A.R.R., I.R.-V., D.S.)."},{"name":"Inmunotek S.L., Alcal\u00e1 de Henares, Spain (S.M.-C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9018-5701","authenticated-orcid":true,"given":"Elena","family":"Hern\u00e1ndez-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.G., V.N., M.F.-M., P.F.-B., E.M.-R., S.M.-C., E.H.-G., M.R.-T., A.R.-R., C.R.-R., A.B., A.R.R., I.R.-V., D.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Rodrigo-Tapias","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.G., V.N., M.F.-M., P.F.-B., E.M.-R., S.M.-C., E.H.-G., M.R.-T., A.R.-R., C.R.-R., A.B., A.R.R., I.R.-V., D.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1589-5831","authenticated-orcid":true,"given":"Ana","family":"Rodr\u00edguez-Ronchel","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.G., V.N., M.F.-M., P.F.-B., E.M.-R., S.M.-C., E.H.-G., M.R.-T., A.R.-R., C.R.-R., A.B., A.R.R., I.R.-V., D.S.)."},{"name":"Escuela de Doctorado, Universidad Aut\u00f3noma de Madrid, Spain (M.G., E.M.-R., A.R.-R., C.R.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1407-9245","authenticated-orcid":true,"given":"Carlos","family":"Rela\u00f1o-Rup\u00e9rez","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.G., V.N., M.F.-M., P.F.-B., E.M.-R., S.M.-C., E.H.-G., M.R.-T., A.R.-R., C.R.-R., A.B., A.R.R., I.R.-V., D.S.)."},{"name":"Escuela de Doctorado, Universidad Aut\u00f3noma de Madrid, Spain (M.G., E.M.-R., A.R.-R., C.R.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5565-8561","authenticated-orcid":true,"given":"Stefanie K.","family":"Wculek","sequence":"additional","affiliation":[{"name":"Innate Immune Biology Laboratory, Institute for Research in Biomedicine (Institute for Research in Biomedicine [IRB] Barcelona), The Barcelona Institute of Science and Technology (BIST), Spain (S.K.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5536-566X","authenticated-orcid":true,"given":"Alberto","family":"Benguria","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.G., V.N., M.F.-M., P.F.-B., E.M.-R., S.M.-C., E.H.-G., M.R.-T., A.R.-R., C.R.-R., A.B., A.R.R., I.R.-V., D.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4910-1684","authenticated-orcid":true,"given":"Ana","family":"Dopazo","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain (A.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8980-9193","authenticated-orcid":true,"given":"Sandrine","family":"Henri","sequence":"additional","affiliation":[{"name":"Aix Marseille Universit\u00e9, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM), Consiglio Nazionale delle Ricerche (CNR), Centre d\u2019Immunologie de Marseille-Luminy, France (S.H., B.M.)."},{"name":"INSERM, Centre d\u2019Etude des Pathologies Respiratoires (CEPR), Unit\u00e9 Mixte de Recherche (UMR) 1100, Universit\u00e9 de Tours, France (S.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7575-9017","authenticated-orcid":true,"given":"Suin","family":"Jo","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO (S.J., T.-T.L., K.M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9377-9938","authenticated-orcid":true,"given":"Tian-Tian","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO (S.J., T.-T.L., K.M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1340-9342","authenticated-orcid":true,"given":"Bernard","family":"Malissen","sequence":"additional","affiliation":[{"name":"Aix Marseille Universit\u00e9, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM), Consiglio Nazionale delle Ricerche (CNR), Centre d\u2019Immunologie de Marseille-Luminy, France (S.H., B.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3505-9630","authenticated-orcid":true,"given":"Kenneth M.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO (S.J., T.-T.L., K.M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7539-3844","authenticated-orcid":true,"given":"Almudena R.","family":"Ramiro","sequence":"additional","affiliation":[{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (M.G., V.N., M.F.-M., P.F.-B., E.M.-R., S.M.-C., E.H.-G., M.R.-T., A.R.-R., C.R.-R., A.B., A.R.R., I.R.-V., D.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1444-6268","authenticated-orcid":true,"given":"Susana","family":"Carregal-Romero","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Cooperativa en Biomateriales (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), San Sebastian, Spain (L.F.-M., S.C.-R., J.R.-C.)."},{"name":"Universidad del Pa\u00eds Vasco\/Euskal Herriko Unibertsitatea (UPV\/EHU), Donostia, Spain (L.F.-M., S.C.-R., J.R.-C.)."},{"name":"Ikerbasque, Basque Foundation for Science, Bilbao, Spain (S.C.-R., J.R.-C.)."},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red (CIBER) de Enfermedades Respiratorias (CIBERES), 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