{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T23:38:47Z","timestamp":1792366727570,"version":"4.4.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2018,2,19]],"date-time":"2018-02-19T00:00:00Z","timestamp":1518998400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2018,2,19]],"date-time":"2018-02-19T00:00:00Z","timestamp":1518998400000},"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":[[2018,4]]},"abstract":"<jats:p>\n                    Macrophages are key regulators of liver fibrosis progression and regression in nonalcoholic steatohepatitis (NASH). Liver macrophages comprise resident phagocytes, Kupffer cells, and monocyte\u2010derived cells, which are recruited through the chemokine receptor C\u2010C motif chemokine receptor 2 (CCR2). We aimed at elucidating the therapeutic effects of inhibiting monocyte infiltration in NASH models by using cenicriviroc (CVC), an oral dual chemokine receptor CCR2\/CCR5 antagonist that is under clinical evaluation. Human liver tissues from NASH patients were analyzed for CCR2\n                    <jats:sup>+<\/jats:sup>\n                    macrophages, and administration of CVC was tested in mouse models of steatohepatitis, liver fibrosis progression, and fibrosis regression. In human livers from 17 patients and 4 controls, CCR2\n                    <jats:sup>+<\/jats:sup>\n                    macrophages increased parallel to NASH severity and fibrosis stage, with a concomitant inflammatory polarization of these cluster of differentiation 68\n                    <jats:sup>+<\/jats:sup>\n                    , portal monocyte\u2010derived macrophages (MoMF). Similar to human disease, we observed a massive increase of hepatic MoMF in experimental models of steatohepatitis and liver fibrosis. Therapeutic treatment with CVC significantly reduced the recruitment of hepatic Ly\u20106C\n                    <jats:sup>+<\/jats:sup>\n                    MoMF in all models. In experimental steatohepatitis with obesity, therapeutic CVC application significantly improved insulin resistance and hepatic triglyceride levels. In fibrotic steatohepatitis, CVC treatment ameliorated histological NASH activity and hepatic fibrosis. CVC inhibited the infiltration of Ly\u20106C\n                    <jats:sup>+<\/jats:sup>\n                    monocytes, without direct effects on macrophage polarization, hepatocyte fatty acid metabolism, or stellate cell activation. Importantly, CVC did not delay fibrosis resolution after injury cessation. RNA sequencing analysis revealed that MoMF, but not Kupffer cells, specifically up\u2010regulate multiple growth factors and cytokines associated with fibrosis progression, while Kupffer cells activated pathways related to inflammation initiation and lipid metabolism.\n                    <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>\n                    : Pharmacological inhibition of CCR2\n                    <jats:sup>+<\/jats:sup>\n                    monocyte recruitment efficiently ameliorates insulin resistance, hepatic inflammation, and fibrosis, corroborating the therapeutic potential of CVC in patients with NASH. (H\n                    <jats:sc>epatology<\/jats:sc>\n                    2018;67:1270\u20101283)\n                  <\/jats:p>","DOI":"10.1002\/hep.29544","type":"journal-article","created":{"date-parts":[[2017,9,21]],"date-time":"2017-09-21T12:36:45Z","timestamp":1505997405000},"page":"1270-1283","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":532,"title":["Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis"],"prefix":"10.1097","volume":"67","author":[{"given":"Oliver","family":"Krenkel","sequence":"first","affiliation":[{"name":"Department of Medicine III,University Hospital Aachen,Aachen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Puengel","sequence":"additional","affiliation":[{"name":"Department of Medicine III,University Hospital Aachen,Aachen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Govaere","sequence":"additional","affiliation":[{"name":"Institute of Cellular Medicine,Newcastle University,Newcastle\u2010upon\u2010Tyne,UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali T.","family":"Abdallah","sequence":"additional","affiliation":[{"name":"IZKF Computational Biology Research Group"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana C.","family":"Mossanen","sequence":"additional","affiliation":[{"name":"Department of Medicine III,University Hospital Aachen,Aachen,Germany"},{"name":"Department of Intensive and Intermediate Care,University Hospital Aachen,Aachen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlene","family":"Kohlhepp","sequence":"additional","affiliation":[{"name":"Department of Medicine III,University Hospital Aachen,Aachen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"Liepelt","sequence":"additional","affiliation":[{"name":"Department of Medicine III,University Hospital Aachen,Aachen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Lefebvre","sequence":"additional","affiliation":[{"name":"Allergan,South San Francisco,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Luedde","sequence":"additional","affiliation":[{"name":"Department of Medicine III,University Hospital Aachen,Aachen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claus","family":"Hellerbrand","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry,Friedrich\u2010Alexander University,Erlangen\u2010Nuremberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Weiskirchen","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Longerich","sequence":"additional","affiliation":[{"name":"Institute of Pathology,University Hospital Aachen,Aachen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan G.","family":"Costa","sequence":"additional","affiliation":[{"name":"IZKF Computational Biology Research Group"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quentin M.","family":"Anstee","sequence":"additional","affiliation":[{"name":"Institute of Cellular Medicine,Newcastle University,Newcastle\u2010upon\u2010Tyne,UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Trautwein","sequence":"additional","affiliation":[{"name":"Department of Medicine III,University Hospital Aachen,Aachen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6206-0226","authenticated-orcid":false,"given":"Frank","family":"Tacke","sequence":"additional","affiliation":[{"name":"Department of Medicine III,University Hospital Aachen,Aachen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2018,2,19]]},"reference":[{"key":"hep29544-bib-0001-20260109","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease\u2014meta\u2010analytic assessment of prevalence, incidence, and outcomes","volume":"64","year":"2016","journal-title":"Hepatology"},{"key":"hep29544-bib-0002-20260109","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1016\/S0140-6736(16)30054-X","article-title":"NCD Risk Factor Collaboration. 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