{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T23:54:58Z","timestamp":1793145298299,"version":"4.5.0"},"reference-count":56,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"675","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2022,12,14]]},"abstract":"<jats:p>\n            Immune-mediated bile duct epithelial injury and toxicity of retained hydrophobic bile acids drive disease progression in fibrosing cholangiopathies such as biliary atresia or primary sclerosing cholangitis. Emerging therapies include pharmacological agonists to farnesoid X receptor (FXR), the master regulator of hepatic synthesis, excretion, and intestinal reuptake of bile acids. Unraveling the mechanisms of action of pharmacological FXR agonists in the treatment of sclerosing cholangitis (SC), we found that intestinally restricted FXR activation effectively reduced bile acid pool size but did not improve the SC phenotype in MDR2\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice. In contrast, systemic FXR activation not only lowered bile acid synthesis but also suppressed proinflammatory cytokine production by liver-infiltrating inflammatory cells and blocked progression of hepatobiliary injury. The hepatoprotective activity was linked to suppressed production of IL1\u03b2 and TNF\u03b1 by hepatic macrophages and inhibition of T\n            <jats:sub>H<\/jats:sub>\n            1\/T\n            <jats:sub>H<\/jats:sub>\n            17 lymphocyte polarization. Deletion of FXR in myeloid cells caused aberrant T\n            <jats:sub>H<\/jats:sub>\n            1 and T\n            <jats:sub>H<\/jats:sub>\n            17 lymphocyte responses in diethoxycarbonyl-1,4-dihydrocollidine\u2013induced SC and rendered these mice resistant to the anti-inflammatory and liver protective effects of systemic FXR agonist treatment. Pharmacological FXR activation reduced IL1\u03b2 and IFN\u03b3 production by liver- and blood-derived mononuclear cells from patients with fibrosing cholangiopathies. In conclusion, we demonstrate FXR to control the macrophage-T\n            <jats:sub>H<\/jats:sub>\n            1\/17 axis, which is critically important for the progression of SC. Hepatic macrophages are cellular targets of systemic FXR agonist therapy for cholestatic liver disease.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.abi4354","type":"journal-article","created":{"date-parts":[[2022,12,14]],"date-time":"2022-12-14T18:59:23Z","timestamp":1671044363000},"source":"Crossref","is-referenced-by-count":46,"title":["Farnesoid X receptor antagonizes macrophage-dependent licensing of effector T lymphocytes and progression of sclerosing cholangitis"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5759-3394","authenticated-orcid":true,"given":"Tiffany","family":"Shi","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6957-8044","authenticated-orcid":true,"given":"Astha","family":"Malik","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0490-1047","authenticated-orcid":true,"given":"Annika","family":"Yang vom Hofe","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"Matuschek","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Mullen","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7029-0512","authenticated-orcid":true,"given":"Celine S.","family":"Lages","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4440-7331","authenticated-orcid":true,"given":"Ramesh","family":"Kudira","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruchi","family":"Singh","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wujuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9147-0136","authenticated-orcid":true,"given":"Kenneth D.R.","family":"Setchell","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."},{"name":"Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0421-8483","authenticated-orcid":true,"given":"David","family":"Hildeman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA."},{"name":"Division of Immunobiology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8142-2488","authenticated-orcid":true,"given":"Chandrashekhar","family":"Pasare","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA."},{"name":"Division of Immunobiology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandee","family":"Wagner","sequence":"additional","affiliation":[{"name":"Metacrine Inc., San Diego, CA 92121, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1395-9475","authenticated-orcid":true,"given":"Alexander G.","family":"Miethke","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."},{"name":"Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28965"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/nbm.4065"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00450.2004"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.5b00676"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26447"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28851"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2014.04.003"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.04.031"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.05.038"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31140"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.02.033"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30509"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/liv.13110"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/bmb\/ldaa006"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(03)00104-7"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3760"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.01.047"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.02.006"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.05.023"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30061"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.061133"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.steroids.2013.05.011"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2004.04.009"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2012.07.008"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.13796"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1008942828960"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0162286"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05489-7"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31140"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29676"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.10.035"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.12.018"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2019.12.008"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/2481418"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7115"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.03.020"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10853-2"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-05-844928"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2014.05.009"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1007\/7651_2014_99"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20022"},{"key":"e_1_3_3_43_2","doi-asserted-by":"crossref","first-page":"e789","DOI":"10.1016\/S0618-8278(19)31571-3","article-title":"SAT-341-MET409, an optimized sustained FXR agonist, was safe and well-tolerated in a 14-day phase 1 study in healthy subjects","volume":"70","author":"Chen H. C.","year":"2019","unstructured":"H. C. Chen, E. Bischoff, K.-J. Lee, R. Littler, J. van de Wetering,SAT-341-MET409, an optimized sustained FXR agonist, was safe and well-tolerated in a 14-day phase 1 study in healthy subjects. J. Hepatol.70,e789 (2019).","journal-title":"J. Hepatol."},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)00062-3"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20060537"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27973"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23294"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23042"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph10093834"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.3700219"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.25662"},{"key":"e_1_3_3_52_2","first-page":"e58621","article-title":"Digestion of the murine liver for a flow cytometric analysis of lymphatic endothelial cells","author":"Finlon J. M.","year":"2019","unstructured":"J. M. Finlon, M. A. Burchill, B. A. J. Tamburini,Digestion of the murine liver for a flow cytometric analysis of lymphatic endothelial cells. J. Vis. Exp. ,e58621 (2019).","journal-title":"J. Vis. Exp."},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-59745-019-5_13"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0703340"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2013.12.002"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-527-5_12"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0139655"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.abi4354","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T18:44:13Z","timestamp":1705430653000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.abi4354"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,14]]},"references-count":56,"journal-issue":{"issue":"675","published-print":{"date-parts":[[2022,12,14]]}},"alternative-id":["10.1126\/scitranslmed.abi4354"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.abi4354","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,14]]},"article-number":"eabi4354"}}