{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T02:50:15Z","timestamp":1793155815558,"version":"4.5.0"},"reference-count":66,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T00:00:00Z","timestamp":1741651200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT-175134"],"award-info":[{"award-number":["PJT-175134"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT- 195731"],"award-info":[{"award-number":["PJT- 195731"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Liver fibrosis is a global health problem. IL-17A has proven profibrogenic properties in liver disease making it an interesting therapeutic target. IL-17A is regulated by ROR\u03b3t and produced by Th17 CD4+ and \u03b3\u03b4-T cells. We hypothesized that blocking IL-17A production will limit fibrosis progression by reducing recruitment of inflammatory cells. Herein, we tested the therapeutic potential of 2 novel ROR\u03b3t inverse agonists (2,3 derivatives of 4,5,6,7-tetrahydro-benzothiophene) in a mouse model of CCl4-induced liver injury. C57BL\/6 mice received 2 weekly injections of CCl4 for 4\u2009weeks. As of week 3, mice were treated with the 2 novel inverse agonists (TF-S10 and TF-S14) and GSK805 as a positive control. Mice treated with the inverse agonists showed reduced immune cells infiltrate around the portal and central veins. TF-S14 significantly reduced AST levels (P\u2009&amp;lt;\u20090.05), and all inhibitors led to an improvement in relative liver weight (liver index). Flow cytometry analysis demonstrated that all inhibitors reduced the numbers of intrahepatic lymphocytes (CD4+, CD8+, and \u03b3\u03b4-T cells, P\u2009&amp;lt;\u20090.05), and myeloid (CD11b+) cells (P\u2009=\u20090.04), most significantly eosinophils (P\u2009&amp;lt;\u20090.05). Furthermore, IL-17A production by CD4+ and \u03b3\u03b4-T cells was diminished (P\u2009&amp;lt;\u20090.05 and P\u2009&amp;lt;\u20090. 01, respectively). Finally, livers from inhibitors-treated mice showed decreased markers of hepatic stellate cell activation (desmin and \u0251-smooth muscle actin [\u0251-SMA]) and significantly reduced expression of the profibrogenic genes (Col1a1, Acta, Loxl2, and Tgf\u03b2) (P\u2009&amp;lt;\u20090.001). This was accompanied by diminished collagen deposition as measured by Picrosirius Red staining (P\u2009&amp;lt;\u20090.001). In conclusion, our results suggest that inhibition of the IL-17A pathway could be a promising therapeutic strategy for liver fibrosis.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf014","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T13:38:56Z","timestamp":1741700336000},"page":"1321-1331","source":"Crossref","is-referenced-by-count":11,"title":["Novel ROR\u03b3t inverse agonists limit IL-17-mediated liver inflammation and fibrosis"],"prefix":"10.1093","volume":"214","author":[{"given":"Afrooz","family":"Dabbaghizadeh","sequence":"first","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CRCHUM) , Montr\u00e9al, QC,","place":["Canada"]},{"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Facult\u00e9 de m\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, QC,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Dion","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CRCHUM) , Montr\u00e9al, QC,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yousef","family":"Maali","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CRCHUM) , Montr\u00e9al, QC,","place":["Canada"]},{"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Facult\u00e9 de m\u00e9decine, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, QC,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1578-3875","authenticated-orcid":false,"given":"Ahmed","family":"Fouda","sequence":"additional","affiliation":[{"name":"Division of Surgical and Interventional Science, Department of Surgery, McGill University , Montreal, QC,","place":["Canada"]},{"name":"Division of General Surgery, Section of Transplant Surgery, Department of Surgery, McGill University , Montreal, QC,","place":["Canada"]},{"name":"Research Institute of the McGill University Health Centre , Montr\u00e9al, QC,","place":["Canada"]},{"name":"McGill University Health Centre , Montr\u00e9al, QC,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"B\u00e9dard","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CRCHUM) , Montr\u00e9al, QC,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6750-9026","authenticated-orcid":false,"given":"Gertruda","family":"Evaristo","sequence":"additional","affiliation":[{"name":"Department of Pathology, McGill University Health Centre , Montreal, QC,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghada S","family":"Hassan","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CRCHUM) , Montr\u00e9al, QC,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Tchervenkov","sequence":"additional","affiliation":[{"name":"Division of Surgical and Interventional Science, Department of Surgery, McGill University , Montreal, QC,","place":["Canada"]},{"name":"Division of General Surgery, Section of Transplant Surgery, Department of Surgery, McGill University , Montreal, QC,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8817-8238","authenticated-orcid":false,"given":"Naglaa H","family":"Shoukry","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de 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