{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:15:56Z","timestamp":1791296156886,"version":"4.1.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2013,5,1]],"date-time":"2013-05-01T00:00:00Z","timestamp":1367366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Chronic liver injury characteristically results in hepatic inflammation, which represents a prerequisite for organ fibrosis. Although NKT cells are abundantly present in liver and involved in hepatic inflammation, molecular mechanisms of their recruitment in liver fibrosis remained elusive. We hypothesized that chemokine receptor CXCR6 and its ligand CXCL16 control NKT cell migration and functionality in liver fibrosis. In patients with chronic liver diseases (n = 58), CXCR6 and CXCL16 expression was intrahepatically upregulated compared with controls. In murine liver, Cxcl16 was strongly expressed by endothelium and macrophages, whereas lymphocyte populations (NKT, NK, CD4 T, CD8 T cells) expressed CXCR6. Intravital two-photon microscopy imaging of Cxcr6+\/gfp and Cxcr6gfp\/gfp mice and chemotaxis studies in vitro revealed that CXCR6 specifically controls hepatic NKT cell accumulation during the early response upon experimental liver damage. Hepatic invariant NKT cells expressed distinct proinflammatory cytokines including IFN-\u03b3 and IL-4 upon injury. CXCR6-deficient mice were protected from liver fibrosis progression in two independent experimental models. Macrophage infiltration and protein levels of inflammatory cytokines IFN-\u03b3, TNF-\u03b1, and IL-4 were also reduced in fibrotic livers of Cxcr6\u2212\/\u2212 mice, corroborating that hepatic NKT cells provide essential cytokine signals perpetuating hepatic inflammation and fibrogenesis. Adoptive transfer of NKT cells, but not CD4 T cells, isolated from wild type livers restored hepatic fibrosis in Cxcr6\u2212\/\u2212 mice upon experimental steatohepatitis. Our results demonstrate that hepatic NKT cells accumulate CXCR6-dependent early upon injury, thereby accentuating the inflammatory response in the liver and promoting hepatic fibrogenesis. Interfering with CXCR6\/CXCL16 might therefore bear therapeutic potential in liver fibrosis.<\/jats:p>","DOI":"10.4049\/jimmunol.1202909","type":"journal-article","created":{"date-parts":[[2013,4,18]],"date-time":"2013-04-18T03:02:00Z","timestamp":1366254120000},"page":"5226-5236","source":"Crossref","is-referenced-by-count":248,"title":["Chemokine Receptor CXCR6-Dependent Hepatic NK T Cell Accumulation Promotes Inflammation and Liver Fibrosis"],"prefix":"10.1093","volume":"190","author":[{"given":"Alexander","family":"Wehr","sequence":"first","affiliation":[{"name":"Department of Medicine III, University-Hospital Aachen , 52074 Aachen,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christer","family":"Baeck","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University-Hospital Aachen , 52074 Aachen,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Heymann","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University-Hospital Aachen , 52074 Aachen,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia Maria","family":"Niemietz","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University-Hospital Aachen , 52074 Aachen,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Hammerich","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University-Hospital Aachen , 52074 Aachen,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Martin","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University-Hospital Aachen , 52074 Aachen"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henning W","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University-Hospital Aachen , 52074 Aachen,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Pack","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University-Hospital Aachen , 52074 Aachen"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaus","family":"Gassler","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University-Hospital Aachen , 52074 Aachen,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanishka","family":"Hittatiya","sequence":"additional","affiliation":[{"name":"Department of Pathology, Rheinische Friedrich-Wilhelms-University , Bonn,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University-Hospital Aachen , 52074 Aachen"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Luedde","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University-Hospital Aachen , 52074 Aachen,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Trautwein","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University-Hospital Aachen , 52074 Aachen,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Tacke","sequence":"additional","affiliation":[{"name":"Department of Medicine III, University-Hospital Aachen , 52074 Aachen,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,5,15]]},"reference":[{"key":"2025032407005790300_r1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1172\/JCI24282","article-title":"Liver fibrosis","volume":"115","author":"Bataller","year":"2005","journal-title":"J. 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