{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T14:30:38Z","timestamp":1778509838411,"version":"3.51.4"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81671578"],"award-info":[{"award-number":["81671578"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-025-08315-5","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T21:59:14Z","timestamp":1751407154000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mitigating cardiac allograft vasculopathy in a murine model via CD40-TRAF6 blockade and cyclosporin A synergy"],"prefix":"10.1038","volume":"15","author":[{"given":"Yajun","family":"Huang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junlin","family":"Lai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinfeng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenghao","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yixuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuqi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tian","family":"Xia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yijie","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wai Yen","family":"Yim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangchao","family":"Ding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guohua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"8315_CR1","doi-asserted-by":"crossref","unstructured":"Arkonac, B., and J. Hosenpud. Pathogenesis of cardiac allograft vasculopathy (chronic rejection). The Transplantation and Replacement of Thoracic Organs: The Present Status of Biological and Mechanical Replacement of the Heart and Lungs: 321\u2013331 (1996).","DOI":"10.1007\/978-0-585-34287-0_34"},{"key":"8315_CR2","doi-asserted-by":"publisher","first-page":"2069","DOI":"10.1161\/01.CIR.96.6.2069","volume":"96","author":"M Weis","year":"1997","unstructured":"Weis, M. & von Scheidt, W. Cardiac allograft vasculopathy: A review. Circulation 96, 2069\u20132077 (1997).","journal-title":"Circulation"},{"key":"8315_CR3","doi-asserted-by":"publisher","first-page":"2499","DOI":"10.1073\/pnas.93.6.2499","volume":"93","author":"K Gerritse","year":"1996","unstructured":"Gerritse, K. et al. CD40-CD40 ligand interactions in experimental allergic encephalomyelitis and multiple sclerosis. Proc. Natl. Acad. Sci. 93, 2499\u20132504 (1996).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"8315_CR4","doi-asserted-by":"crossref","unstructured":"Law, C.-L., and I. S. Grewal. Therapeutic interventions targeting CD40L (CD154) and CD40: the opportunities and challenges. Therapeutic Targets of the TNF Superfamily 8\u201336 (2009).","DOI":"10.1007\/978-0-387-89520-8_2"},{"key":"8315_CR5","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/S1567-5688(07)71855-X","volume":"1","author":"A Sarantopoulos","year":"2007","unstructured":"Sarantopoulos, A. et al. YI-845 CD40\/CD40L in dyslipidemic patients with rheumatoid arthritis (RA). The immunomodulating effect of simvastatin. Atherosclerosis (Supplements) (Component) 1, 224 (2007).","journal-title":"Atherosclerosis (Supplements) (Component)"},{"key":"8315_CR6","doi-asserted-by":"publisher","first-page":"245","DOI":"10.4161\/auto.3717","volume":"3","author":"CS Subauste","year":"2007","unstructured":"Subauste, C. S., Andrade, R. M. & Wessendarp, M. CD40-TRAF6 and autophagy-dependant anti-microbial activity in macrophages. Autophagy 3, 245\u2013248 (2007).","journal-title":"Autophagy"},{"key":"8315_CR7","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1111\/imr.12302","volume":"266","author":"MC Walsh","year":"2015","unstructured":"Walsh, M. C., Lee, J. & Choi, Y. Tumor necrosis factor receptor-associated factor 6 (TRAF 6) regulation of development, function, and homeostasis of the immune system. Immunol. Rev. 266, 72\u201392 (2015).","journal-title":"Immunol. Rev."},{"key":"8315_CR8","first-page":"4596","volume":"111","author":"MM Donners","year":"2008","unstructured":"Donners, M. M. et al. The CD40-TRAF6 axis is the key regulator of the CD40\/CD40L system in neointima formation and arterial remodeling. Blood J. Am. Soc. Hematol. 111, 4596\u20134604 (2008).","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"8315_CR9","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1097\/MOT.0000000000000209","volume":"20","author":"S Salehi","year":"2015","unstructured":"Salehi, S. & Reed, E. F. The divergent roles of macrophages in solid organ transplantation. Curr. Opin. Organ Tran. 20, 446\u2013453 (2015).","journal-title":"Curr. Opin. Organ Tran."},{"key":"8315_CR10","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1111\/ajt.14543","volume":"18","author":"Y Zhao","year":"2018","unstructured":"Zhao, Y. et al. Macrophage subpopulations and their impact on chronic allograft rejection versus graft acceptance in a mouse heart transplant model. Am. J. Transplant. 18, 604\u2013616 (2018).","journal-title":"Am. J. Transplant."},{"key":"8315_CR11","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1016\/j.jacc.2017.11.055","volume":"71","author":"TT Seijkens","year":"2018","unstructured":"Seijkens, T. T. et al. Targeting CD40-induced TRAF6 signaling in macrophages reduces atherosclerosis. J. Am. Coll. Cardiol. 71, 527\u2013542 (2018).","journal-title":"J. Am. Coll. Cardiol."},{"key":"8315_CR12","doi-asserted-by":"publisher","first-page":"1582","DOI":"10.21037\/atm-20-2899","volume":"8","author":"Y Huang","year":"2020","unstructured":"Huang, Y. et al. Inhibition of S-adenosyl-L-homocysteine hydrolase alleviates alloimmune response by down-regulating CD4(+) T-cell activation in a mouse heart transplantation model. Ann. Transl. Med. 8, 1582 (2020).","journal-title":"Ann. Transl. Med."},{"key":"8315_CR13","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).","journal-title":"Genome Biol."},{"key":"8315_CR14","first-page":"100141","volume":"2","author":"T Wu","year":"2021","unstructured":"Wu, T. et al. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb.) 2, 100141 (2021).","journal-title":"Innovation (Camb.)"},{"key":"8315_CR15","doi-asserted-by":"publisher","unstructured":"Hua, X. et al. Single-cell RNA sequencing to dissect the immunological network of autoimmune myocarditis. Circulation. 142(4), 384\u2013400. https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.119.043545 (2020).","DOI":"10.1161\/CIRCULATIONAHA.119.043545"},{"key":"8315_CR16","doi-asserted-by":"publisher","first-page":"6242","DOI":"10.7150\/thno.75543","volume":"12","author":"Z Chen","year":"2022","unstructured":"Chen, Z. et al. Single-Cell RNA sequencing reveals immune cell dynamics and local intercellular communication in acute murine cardiac allograft rejection. Theranostics 12, 6242\u20136257 (2022).","journal-title":"Theranostics"},{"key":"8315_CR17","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/nbt.4096","volume":"36","author":"A Butler","year":"2018","unstructured":"Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411\u2013420 (2018).","journal-title":"Nat. Biotechnol."},{"key":"8315_CR18","doi-asserted-by":"publisher","first-page":"979","DOI":"10.12688\/f1000research.73600.2","volume":"10","author":"Pierre-Luc Germain","year":"2021","unstructured":"Germain, P. L., Lun, A., Garcia Meixide, C., Macnair, W. & Robinson, M. D. Doublet identification in single-cell sequencing data using scDblFinder. F1000Res. 10, 979. https:\/\/doi.org\/10.12688\/f1000research.73600.2 (2021).","journal-title":"F1000Research"},{"key":"8315_CR19","doi-asserted-by":"publisher","unstructured":"Yang, S. et al. Decontamination of ambient RNA in single-cell RNA-seq with DecontX. Genome Biol. 21(1). https:\/\/doi.org\/10.1186\/s13059-020-1950-6 (2020).","DOI":"10.1186\/s13059-020-1950-6"},{"key":"8315_CR20","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","volume":"16","author":"I Korsunsky","year":"2019","unstructured":"Korsunsky, I. et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat. Methods 16, 1289\u20131296 (2019).","journal-title":"Nat. Methods"},{"key":"8315_CR21","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1093\/rheumatology\/kel229","volume":"46","author":"D Daoussis","year":"2007","unstructured":"Daoussis, D., Antonopoulos, I., Andonopoulos, A. P. & Liossis, S. N. Increased expression of CD154 (CD40L) on stimulated T-cells from patients with psoriatic arthritis. Rheumatology (Oxford) 46, 227\u2013231 (2007).","journal-title":"Rheumatology (Oxford)"},{"key":"8315_CR22","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1097\/00007890-200008150-00018","volume":"70","author":"A Shoker","year":"2000","unstructured":"Shoker, A., George, D., Yang, H. & Baltzan, M. Heightened CD40 ligand gene expression in peripheral CD4+ T cells from patients with kidney allograft rejection. Transplantation 70, 497\u2013505 (2000).","journal-title":"Transplantation"},{"key":"8315_CR23","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1097\/00075200-200109000-00001","volume":"6","author":"JJ Yun","year":"2001","unstructured":"Yun, J. J., Fischbein, M. P., Laks, H. & Ardehali, A. Chronic rejection of transplanted hearts. Curr. Opin. Organ Tran. 6, 205\u2013210 (2001).","journal-title":"Curr. Opin. Organ Tran."},{"key":"8315_CR24","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/S0966-3274(96)80033-5","volume":"4","author":"D Alexander","year":"1996","unstructured":"Alexander, D., Pearson, T., Hendrix, R., Ritchie, S. & Larsen, C. Analysis of effector mechanisms in murine cardiac allograft rejection. Transpl. Immunol. 4, 46\u201348 (1996).","journal-title":"Transpl. Immunol."},{"key":"8315_CR25","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1111\/j.1432-2277.2008.00676.x","volume":"21","author":"N Schaefer","year":"2008","unstructured":"Schaefer, N. et al. Role of resident macrophages in the immunologic response and smooth muscle dysfunction during acute allograft rejection after intestinal transplantation. Transpl. Int. 21, 778\u2013791 (2008).","journal-title":"Transpl. Int."},{"key":"8315_CR26","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1007\/s40472-016-0130-9","volume":"3","author":"Y Liu","year":"2016","unstructured":"Liu, Y., Kloc, M. & Li, X. C. Macrophages as effectors of acute and chronic allograft injury. Curr. Transpl. Rep. 3, 303\u2013312 (2016).","journal-title":"Curr. Transpl. Rep."},{"key":"8315_CR27","doi-asserted-by":"crossref","unstructured":"Di Meo, S., T. T. Reed, P. Venditti, and V. M. Victor. Role of ROS and RNS sources in physiological and pathological conditions. Oxidative medicine and cellular longevity 2016. (2016).","DOI":"10.1155\/2016\/1245049"},{"key":"8315_CR28","doi-asserted-by":"publisher","first-page":"2675","DOI":"10.1111\/j.1600-6143.2007.01997.x","volume":"7","author":"W Kitchens","year":"2007","unstructured":"Kitchens, W. et al. Macrophage depletion suppresses cardiac allograft vasculopathy in mice. Am. J. Transplant. 7, 2675\u20132682 (2007).","journal-title":"Am. J. Transplant."},{"key":"8315_CR29","doi-asserted-by":"publisher","first-page":"S42","DOI":"10.1016\/j.healun.2019.01.087","volume":"38","author":"L Holzhauser","year":"2019","unstructured":"Holzhauser, L. et al. Cardiac allograft vasculopathy is linked to impaired generation of regulatory M2 macrophages. J. Heart Lung Transplant. 38, S42 (2019).","journal-title":"J. Heart Lung Transplant."},{"key":"8315_CR30","doi-asserted-by":"publisher","first-page":"2703","DOI":"10.4049\/jimmunol.1102997","volume":"188","author":"W Liu","year":"2012","unstructured":"Liu, W., Xiao, X., Demirci, G., Madsen, J. & Li, X. C. Innate NK cells and macrophages recognize and reject allogeneic nonself in vivo via different mechanisms. J. Immunol. 188, 2703\u20132711 (2012).","journal-title":"J. Immunol."},{"key":"8315_CR31","doi-asserted-by":"publisher","first-page":"8","DOI":"10.4049\/jimmunol.156.1.8","volume":"156","author":"RD Stout","year":"1996","unstructured":"Stout, R. D., Suttles, J., Xu, J., Grewal, I. S. & Flavell, R. A. Impaired T cell-mediated macrophage activation in CD40 ligand-deficient mice. J. Immunol. (Baltimore, Md.: 1950) 156, 8\u201311 (1996).","journal-title":"J. Immunol. (Baltimore, Md.: 1950)"},{"key":"8315_CR32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12974-017-0875-9","volume":"14","author":"SA Aarts","year":"2017","unstructured":"Aarts, S. A. et al. Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation. J. Neuroinflammation 14, 1\u201314 (2017).","journal-title":"J. Neuroinflammation"},{"key":"8315_CR33","doi-asserted-by":"publisher","first-page":"6758","DOI":"10.1038\/sj.onc.1209943","volume":"25","author":"MS Hayden","year":"2006","unstructured":"Hayden, M. S., West, A. P. & Ghosh, S. NF-kappaB and the immune response. Oncogene 25, 6758\u20136780 (2006).","journal-title":"Oncogene"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-08315-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-08315-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-08315-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T21:59:16Z","timestamp":1751407156000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-08315-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,1]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["8315"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-08315-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,1]]},"assertion":[{"value":"16 December 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 June 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 July 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All experiments were conducted according to the Guide of the Care and Use of Laboratory Animals of the Laboratory Animal Ethical Commission of Tongji Medical College, Huazhong University of Science and Technology (IACUC Number: 2358).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}},{"value":"All authors approved the final manuscript and the submission to this journal.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"22327"}}