{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T23:31:49Z","timestamp":1783467109421,"version":"3.55.0"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T00:00:00Z","timestamp":1706140800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T00:00:00Z","timestamp":1706140800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100008538","name":"PSC Partners Seeking a Cure","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008538","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["KL2 TR002379"],"award-info":[{"award-number":["KL2 TR002379"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK124182"],"award-info":[{"award-number":["DK124182"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIDDK-funded Optical Microscopy Core of Mayo Clinic Center for Cell Signaling in Gastroenterology","award":["P30DK084567"],"award-info":[{"award-number":["P30DK084567"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Ductular reactive (DR) cells exacerbate cholestatic liver injury and fibrosis. Herein, we posit that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) emanates from recruited macrophages and restrains DR cell expansion, thereby limiting cholestatic liver injury. Wild type (WT), <jats:italic>Trail<\/jats:italic><jats:sup><jats:italic>fl\/fl<\/jats:italic><\/jats:sup> and myeloid-specific <jats:italic>Trail<\/jats:italic> deleted (<jats:italic>Trail<\/jats:italic><jats:sup><jats:italic>\u0394mye<\/jats:italic><\/jats:sup>) C57BL\/6 mice were exposed to DDC diet-induced cholestatic liver injury, which induced hepatomegaly and liver injury as compared to control diet-fed mice. However, parameters of liver injury, fibrosis, and inflammation were all increased in the <jats:italic>Trail<\/jats:italic><jats:sup><jats:italic>\u0394mye<\/jats:italic><\/jats:sup> mice as compared to the WT and <jats:italic>Trail<\/jats:italic><jats:sup><jats:italic>fl\/fl<\/jats:italic><\/jats:sup> mice. High dimensional mass cytometry indicated that cholestasis resulted in increased hepatic recruitment of subsets of macrophages and neutrophils in the <jats:italic>Trail<\/jats:italic><jats:sup><jats:italic>\u0394mye<\/jats:italic><\/jats:sup> mice. Spatial transcriptomics analysis revealed that the PanCK<jats:sup>+<\/jats:sup> cholangiocytes from <jats:italic>Trail<\/jats:italic><jats:sup><jats:italic>\u0394mye<\/jats:italic><\/jats:sup> mice had increased expression of the known myeloid attractants <jats:italic>S100a8, Cxcl5, Cx3cl1,<\/jats:italic> and <jats:italic>Cxcl1.<\/jats:italic> Additionally, in situ hybridization of <jats:italic>Cxcl1,<\/jats:italic> a potent neutrophil chemoattractant, demonstrated an increased expression in CK19<jats:sup>+<\/jats:sup> cholangiocytes of <jats:italic>Trail<\/jats:italic><jats:sup><jats:italic>\u0394mye<\/jats:italic><\/jats:sup> mice. Collectively, these data suggest that TRAIL from myeloid cells, particularly macrophages, restrains a subset of DR cells (i.e., <jats:italic>Cxcl1<\/jats:italic> positive cells), limiting liver inflammation and fibrosis. Reprogramming macrophages to express TRAIL may be salutary in cholestasis.<\/jats:p>","DOI":"10.1038\/s41598-024-52710-3","type":"journal-article","created":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T07:02:46Z","timestamp":1706166166000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) deletion in myeloid cells augments cholestatic liver injury"],"prefix":"10.1038","volume":"14","author":[{"given":"Anuradha","family":"Krishnan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazli Begum","family":"Ozturk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyel A.","family":"Cutshaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Eugenia","family":"Guicciardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kitagataya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsta E.","family":"Olson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin D.","family":"Pavelko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Sherman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander Q.","family":"Wixom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nidhi","family":"Jalan-Sakrikar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Baez-Faria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florencia","family":"Gutierrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory J.","family":"Gores","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,25]]},"reference":[{"key":"52710_CR1","doi-asserted-by":"publisher","first-page":"2501","DOI":"10.1056\/NEJMc1613273","volume":"375","author":"KN Lazaridis","year":"2016","unstructured":"Lazaridis, K. N. & LaRusso, N. F. Primary sclerosing cholangitis. N. Engl. J. Med. 375, 2501\u20132502. https:\/\/doi.org\/10.1056\/NEJMc1613273 (2016).","journal-title":"N. Engl. J. Med."},{"key":"52710_CR2","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1038\/s41575-019-0125-y","volume":"16","author":"JM Banales","year":"2019","unstructured":"Banales, J. M. et al. Cholangiocyte pathobiology. Nat. Rev. Gastroenterol. Hepatol. 16, 269\u2013281. https:\/\/doi.org\/10.1038\/s41575-019-0125-y (2019).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"52710_CR3","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1038\/labinvest.2017.63","volume":"97","author":"L Loarca","year":"2017","unstructured":"Loarca, L. et al. Development and characterization of cholangioids from normal and diseased human cholangiocytes as an in vitro model to study primary sclerosing cholangitis. Lab. Investig. 97, 1385\u20131396. https:\/\/doi.org\/10.1038\/labinvest.2017.63 (2017).","journal-title":"Lab. Investig."},{"key":"52710_CR4","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1002\/hep.30150","volume":"69","author":"K Sato","year":"2019","unstructured":"Sato, K. et al. Ductular reaction in liver diseases: Pathological mechanisms and translational significances. Hepatology 69, 420\u2013430. https:\/\/doi.org\/10.1002\/hep.30150 (2019).","journal-title":"Hepatology"},{"key":"52710_CR5","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1002\/hep.31067","volume":"71","author":"ME Guicciardi","year":"2020","unstructured":"Guicciardi, M. E., Trussoni, C. E., LaRusso, N. F. & Gores, G. J. The spectrum of reactive cholangiocytes in primary sclerosing cholangitis. Hepatology 71, 741\u2013748. https:\/\/doi.org\/10.1002\/hep.31067 (2020).","journal-title":"Hepatology"},{"key":"52710_CR6","doi-asserted-by":"publisher","first-page":"1853","DOI":"10.1002\/hep.24613","volume":"54","author":"AS Gouw","year":"2011","unstructured":"Gouw, A. S., Clouston, A. D. & Theise, N. D. Ductular reactions in human liver: Diversity at the interface. Hepatology 54, 1853\u20131863. https:\/\/doi.org\/10.1002\/hep.24613 (2011).","journal-title":"Hepatology"},{"key":"52710_CR7","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1016\/j.jhep.2018.05.018","volume":"69","author":"ME Guicciardi","year":"2018","unstructured":"Guicciardi, M. E. et al. Macrophages contribute to the pathogenesis of sclerosing cholangitis in mice. J. Hepatol. 69, 676\u2013686. https:\/\/doi.org\/10.1016\/j.jhep.2018.05.018 (2018).","journal-title":"J. Hepatol."},{"key":"52710_CR8","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1172\/JCI22675","volume":"115","author":"JS Duffield","year":"2005","unstructured":"Duffield, J. S. et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Investig. 115, 56\u201365. https:\/\/doi.org\/10.1172\/JCI22675 (2005).","journal-title":"J. Clin. Investig."},{"key":"52710_CR9","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/bs.ircmb.2020.02.002","volume":"351","author":"D Stohr","year":"2020","unstructured":"Stohr, D., Jeltsch, A. & Rehm, M. TRAIL receptor signaling: From the basics of canonical signal transduction toward its entanglement with ER stress and the unfolded protein response. Int. Rev. Cell. Mol. Biol. 351, 57\u201399. https:\/\/doi.org\/10.1016\/bs.ircmb.2020.02.002 (2020).","journal-title":"Int. Rev. Cell. Mol. Biol."},{"key":"52710_CR10","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1038\/cr.2009.57","volume":"19","author":"W Tang","year":"2009","unstructured":"Tang, W. et al. TRAIL receptor mediates inflammatory cytokine release in an NF-kappaB-dependent manner. Cell Res. 19, 758\u2013767. https:\/\/doi.org\/10.1038\/cr.2009.57 (2009).","journal-title":"Cell Res."},{"key":"52710_CR11","doi-asserted-by":"publisher","first-page":"1284","DOI":"10.1016\/j.ajpath.2020.02.013","volume":"190","author":"A Krishnan","year":"2020","unstructured":"Krishnan, A. et al. Tumor necrosis factor-related apoptosis-inducing ligand receptor deficiency promotes the ductular reaction, macrophage accumulation, and hepatic fibrosis in the Abcb4(-\/-) Mouse. Am. J. Pathol. 190, 1284\u20131297. https:\/\/doi.org\/10.1016\/j.ajpath.2020.02.013 (2020).","journal-title":"Am. J. Pathol."},{"key":"52710_CR12","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1152\/physrev.00045.2017","volume":"99","author":"C Dostert","year":"2019","unstructured":"Dostert, C., Grusdat, M., Letellier, E. & Brenner, D. The TNF family of ligands and receptors: Communication modules in the immune system and beyond. Physiol. Rev. 99, 115\u2013160. https:\/\/doi.org\/10.1152\/physrev.00045.2017 (2019).","journal-title":"Physiol. Rev."},{"key":"52710_CR13","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41423-020-00558-8","volume":"18","author":"Y Wen","year":"2021","unstructured":"Wen, Y., Lambrecht, J., Ju, C. & Tacke, F. Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities. Cell Mol. Immunol. 18, 45\u201356. https:\/\/doi.org\/10.1038\/s41423-020-00558-8 (2021).","journal-title":"Cell Mol. Immunol."},{"key":"52710_CR14","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1016\/j.jhep.2016.05.037","volume":"65","author":"L Beattie","year":"2016","unstructured":"Beattie, L. et al. Bone marrow-derived and resident liver macrophages display unique transcriptomic signatures but similar biological functions. J. Hepatol. 65, 758\u2013768. https:\/\/doi.org\/10.1016\/j.jhep.2016.05.037 (2016).","journal-title":"J. Hepatol."},{"key":"52710_CR15","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1038\/s41586-019-1631-3","volume":"575","author":"P Ramachandran","year":"2019","unstructured":"Ramachandran, P. et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512\u2013518. https:\/\/doi.org\/10.1038\/s41586-019-1631-3 (2019).","journal-title":"Nature"},{"key":"52710_CR16","doi-asserted-by":"publisher","first-page":"eabl7482","DOI":"10.1126\/sciimmunol.abl7482","volume":"7","author":"DE Sanin","year":"2022","unstructured":"Sanin, D. E. et al. A common framework of monocyte-derived macrophage activation. Sci. Immunol. 7, eabl7482. https:\/\/doi.org\/10.1126\/sciimmunol.abl7482 (2022).","journal-title":"Sci. Immunol."},{"key":"52710_CR17","doi-asserted-by":"publisher","first-page":"2445","DOI":"10.1172\/JCI78585","volume":"125","author":"S Jors","year":"2015","unstructured":"Jors, S. et al. Lineage fate of ductular reactions in liver injury and carcinogenesis. J. Clin. Investig. 125, 2445\u20132457. https:\/\/doi.org\/10.1172\/JCI78585 (2015).","journal-title":"J. Clin. Investig."},{"key":"52710_CR18","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1101\/gad.2029411","volume":"25","author":"C Dorrell","year":"2011","unstructured":"Dorrell, C. et al. Prospective isolation of a bipotential clonogenic liver progenitor cell in adult mice. Genes Dev. 25, 1193\u20131203. https:\/\/doi.org\/10.1101\/gad.2029411 (2011).","journal-title":"Genes Dev."},{"key":"52710_CR19","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000000270","author":"A Guillot","year":"2023","unstructured":"Guillot, A. et al. Mapping the hepatic immune landscape identifies monocytic macrophages as key drivers of steatohepatitis and cholangiopathy progression. Hepatology https:\/\/doi.org\/10.1097\/HEP.0000000000000270 (2023).","journal-title":"Hepatology"},{"key":"52710_CR20","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1002\/hep.31211","volume":"72","author":"AI Azad","year":"2020","unstructured":"Azad, A. I. et al. Targeted apoptosis of ductular reactive cells reduces hepatic fibrosis in a mouse model of cholestasis. Hepatology 72, 1013\u20131028. https:\/\/doi.org\/10.1002\/hep.31211 (2020).","journal-title":"Hepatology"},{"key":"52710_CR21","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1097\/MOG.0000000000000814","volume":"38","author":"A Bruneau","year":"2022","unstructured":"Bruneau, A., Guillot, A. & Tacke, F. Macrophages in cholangiopathies. Curr. Opin. Gastroenterol. 38, 114\u2013120. https:\/\/doi.org\/10.1097\/MOG.0000000000000814 (2022).","journal-title":"Curr. Opin. Gastroenterol."},{"key":"52710_CR22","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1007\/s00441-017-2785-7","volume":"371","author":"J Wang","year":"2018","unstructured":"Wang, J. Neutrophils in tissue injury and repair. Cell Tissue Res. 371, 531\u2013539. https:\/\/doi.org\/10.1007\/s00441-017-2785-7 (2018).","journal-title":"Cell Tissue Res."},{"key":"52710_CR23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2023.05.045","author":"S Arino","year":"2023","unstructured":"Arino, S. et al. Ductular reaction-associated neutrophils promote biliary epithelium proliferation in chronic liver disease. J. Hepatol. https:\/\/doi.org\/10.1016\/j.jhep.2023.05.045 (2023).","journal-title":"J. Hepatol."},{"key":"52710_CR24","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1038\/nri2779","volume":"10","author":"O Soehnlein","year":"2010","unstructured":"Soehnlein, O. & Lindbom, L. Phagocyte partnership during the onset and resolution of inflammation. Nat. Rev. Immunol. 10, 427\u2013439. https:\/\/doi.org\/10.1038\/nri2779 (2010).","journal-title":"Nat. Rev. Immunol."},{"key":"52710_CR25","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/s41423-020-0412-0","volume":"17","author":"M Metzemaekers","year":"2020","unstructured":"Metzemaekers, M., Gouwy, M. & Proost, P. Neutrophil chemoattractant receptors in health and disease: Double-edged swords. Cell Mol. Immunol. 17, 433\u2013450. https:\/\/doi.org\/10.1038\/s41423-020-0412-0 (2020).","journal-title":"Cell Mol. Immunol."},{"key":"52710_CR26","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.isci.2018.12.037","volume":"12","author":"SP Cartland","year":"2019","unstructured":"Cartland, S. P. et al. TRAIL-expressing monocyte\/macrophages are critical for reducing inflammation and atherosclerosis. iScience 12, 41\u201352. https:\/\/doi.org\/10.1016\/j.isci.2018.12.037 (2019).","journal-title":"iScience"},{"key":"52710_CR27","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1016\/j.jhep.2022.05.044","volume":"77","author":"I Labiano","year":"2022","unstructured":"Labiano, I. et al. TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation. J. Hepatol. 77, 991\u20131004. https:\/\/doi.org\/10.1016\/j.jhep.2022.05.044 (2022).","journal-title":"J. Hepatol."},{"key":"52710_CR28","doi-asserted-by":"publisher","first-page":"18624","DOI":"10.1074\/jbc.M112.442954","volume":"288","author":"H Malhi","year":"2013","unstructured":"Malhi, H. et al. C\/EBP homologous protein-induced macrophage apoptosis protects mice from steatohepatitis. J. Biol. Chem. 288, 18624\u201318642. https:\/\/doi.org\/10.1074\/jbc.M112.442954 (2013).","journal-title":"J. Biol. Chem."},{"key":"52710_CR29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1005112","volume":"12","author":"H Chen","year":"2016","unstructured":"Chen, H. et al. Cytofkit: A bioconductor package for an integrated mass cytometry data analysis pipeline. PLoS Comput. Biol. 12, e1005112. https:\/\/doi.org\/10.1371\/journal.pcbi.1005112 (2016).","journal-title":"PLoS Comput. Biol."},{"key":"52710_CR30","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1038\/ni.3006","volume":"15","author":"B Becher","year":"2014","unstructured":"Becher, B. et al. High-dimensional analysis of the murine myeloid cell system. Nat. Immunol. 15, 1181\u20131189. https:\/\/doi.org\/10.1038\/ni.3006 (2014).","journal-title":"Nat. Immunol."},{"key":"52710_CR31","doi-asserted-by":"publisher","first-page":"W566","DOI":"10.1093\/nar\/gkv468","volume":"43","author":"T Metsalu","year":"2015","unstructured":"Metsalu, T. & Vilo, J. ClustVis: A web tool for visualizing clustering of multivariate data using principal component analysis and heatmap. Nucleic Acids Res. 43, W566-570. https:\/\/doi.org\/10.1093\/nar\/gkv468 (2015).","journal-title":"Nucleic Acids Res."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-52710-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-52710-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-52710-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T07:22:00Z","timestamp":1706167320000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-52710-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,25]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["52710"],"URL":"https:\/\/doi.org\/10.1038\/s41598-024-52710-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,25]]},"assertion":[{"value":"14 July 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 January 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 January 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2145"}}