{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:37:36Z","timestamp":1790660256514,"version":"4.1.0"},"reference-count":32,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2016,1,16]],"date-time":"2016-01-16T00:00:00Z","timestamp":1452902400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2016,1,16]],"date-time":"2016-01-16T00:00:00Z","timestamp":1452902400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2016,3]]},"abstract":"<jats:p>Congenital hepatic fibrosis (CHF) is a disease of the biliary epithelium characterized by bile duct changes resembling ductal plate malformations and by progressive peribiliary fibrosis, in the absence of overt necroinflammation. Progressive liver fibrosis leads to portal hypertension and liver failure; however, the mechanisms leading to fibrosis in CHF remain elusive. CHF is caused by mutations in<jats:italic toggle=\"yes\">PKHD1<\/jats:italic>, a gene encoding for fibrocystin, a ciliary protein expressed in cholangiocytes. Using a fibrocystin\u2010defective (<jats:italic toggle=\"yes\">Pkhd1<\/jats:italic><jats:sup>del4\/del4<\/jats:sup>) mouse, which is orthologous of CHF, we show that<jats:italic toggle=\"yes\">Pkhd1<\/jats:italic><jats:sup>del4\/del4<\/jats:sup>cholangiocytes are characterized by a \u03b2\u2010catenin\u2010dependent secretion of a range of chemokines, including chemokine (C\u2010X\u2010C motif) ligands 1, 10, and 12, which stimulate bone marrow\u2010derived macrophage recruitment. We also show that<jats:italic toggle=\"yes\">Pkhd1<\/jats:italic><jats:sup>del4\/del4<\/jats:sup>cholangiocytes, in turn, respond to proinflammatory cytokines released by macrophages by up\u2010regulating \u03b1v\u03b26 integrin, an activator of latent local transforming growth factor\u2010\u03b21. While the macrophage infiltrate is initially dominated by the M1 phenotype, the profibrogenic M2 phenotype increases with disease progression, along with the number of portal myofibroblasts. Consistent with these findings, clodronate\u2010induced macrophage depletion results in a significant reduction of portal fibrosis and portal hypertension as well as of liver cysts.<jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>Fibrosis can be initiated by an epithelial cell dysfunction, leading to low\u2010grade inflammation, macrophage recruitment, and collagen deposition; these findings establish a new paradigm for biliary fibrosis and represent a model to understand the relationship between cell dysfunction, parainflammation, liver fibrosis, and macrophage polarization over time. (H<jats:sc>epatology<\/jats:sc>2016;63:965\u2013982)<\/jats:p>","DOI":"10.1002\/hep.28382","type":"journal-article","created":{"date-parts":[[2015,12,9]],"date-time":"2015-12-09T07:08:30Z","timestamp":1449644910000},"page":"965-982","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":99,"title":["Macrophage recruitment by fibrocystin\u2010defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis"],"prefix":"10.1097","volume":"63","author":[{"given":"Luigi","family":"Locatelli","sequence":"first","affiliation":[{"name":"Department of Surgery and Translational Medicine,University of Milan\u2010Bicocca,Milan,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Cadamuro","sequence":"additional","affiliation":[{"name":"Department of Surgery and Translational Medicine,University of Milan\u2010Bicocca,Milan,Italy"},{"name":"Department of Molecular 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Milan\u2010Bicocca,Milan,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yury","family":"Popov","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Beth Israel Deaconess Medical Center,Harvard Medical School,Boston,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Scirpo","sequence":"additional","affiliation":[{"name":"Department of Surgery and Translational Medicine,University of Milan\u2010Bicocca,Milan,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"De Matteis","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine,University of Padua School of Medicine,Padua,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariangela","family":"Amenduni","sequence":"additional","affiliation":[{"name":"Section of Digestive Diseases,Yale University,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Pietrobattista","sequence":"additional","affiliation":[{"name":"Liver Unit, Bambino Ges\u00f9 Pediatric Hospital,IRCSS,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliano","family":"Torre","sequence":"additional","affiliation":[{"name":"Liver Unit, Bambino Ges\u00f9 Pediatric Hospital,IRCSS,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Detlef","family":"Schuppan","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Beth Israel Deaconess Medical Center,Harvard Medical School,Boston,MA"},{"name":"Institute of Translational Immunology,Johannes Gutenberg University,Mainz,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Fabris","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine,University of Padua School of 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