{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T11:08:10Z","timestamp":1789729690887,"version":"4.0.1"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":792,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>Chemokine receptors mediate migration of immune cells into the liver, thereby promoting liver inflammation. C-C motif chemokine receptor (CCR) 9<jats:sup>+<\/jats:sup> macrophages are crucial in the pathogenesis of acute liver inflammation, but the role and underlying mechanisms of this macrophage subset in chronic liver injury and subsequent liver fibrosis are not fully understood. We confirmed that tumor necrosis factor alpha (TNF-\u03b1)-producing CCR9<jats:sup>+<\/jats:sup> macrophages accumulated during the initiation of carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>)-induced liver injury, and CCR9 deficiency attenuated the degree of liver damage. Accumulation of CCR9<jats:sup>+<\/jats:sup> macrophages persisted prominently during the process of liver fibrosis induced by repetitive CCl<jats:sub>4<\/jats:sub> or thioacetamide (TAA)\/leptin administration. Increased CCR9 expression was also found on activated hepatic stellate cells (HSCs). Importantly, experimental liver fibrosis was significantly ameliorated in <jats:italic toggle=\"yes\">CCR9<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup> mice compared with wild-type (WT) mice, assessed by \u03b1-smooth muscle actin (\u03b1-SMA) immunostain, Sirius red staining, and messenger RNA (mRNA) expression levels of \u03b1-<jats:italic toggle=\"yes\">SMA, collagen 1\u03b11, transforming growth factor (TGF)-\u03b21<\/jats:italic>, and <jats:italic toggle=\"yes\">tissue inhibitor of metalloproteinase (TIMP)-1<\/jats:italic>. Accumulated CD11b<jats:sup>+<\/jats:sup> macrophages in CCl<jats:sub>4<\/jats:sub>-treated WT mice showed marked increases in <jats:italic toggle=\"yes\">TNF, NO synthase-2<\/jats:italic>, and <jats:italic toggle=\"yes\">TGF-\u03b21<\/jats:italic> mRNA expression compared with <jats:italic toggle=\"yes\">CCR9<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup> mice, implying proinflammatory and profibrogenic properties. Hepatic CD11b<jats:sup>+<\/jats:sup> macrophages from CCl<jats:sub>4<\/jats:sub>-treated WT mice (i.e., CCR9<jats:sup>+<\/jats:sup> macrophages), but not CD8<jats:sup>+<\/jats:sup> T lymphocytes or non-CD11b<jats:sup>+<\/jats:sup> cells, significantly activated HSCs <jats:italic toggle=\"yes\">in vitro<\/jats:italic> compared with those from <jats:italic toggle=\"yes\">CCR9<\/jats:italic>\n                                 <jats:sup>\u2212\/\u2212<\/jats:sup> mice. TNF-\u03b1 or TGF-\u03b21 antagonism attenuated CCR9<jats:sup>+<\/jats:sup> macrophage-induced HSC activation. Furthermore, C-C motif chemokine ligand (CCL) 25 mediated migration and, to a lesser extent, activation of HSCs <jats:italic toggle=\"yes\">in vitro<\/jats:italic>. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Accumulated CD11b<jats:sup>+<\/jats:sup> macrophages are critical for activating HSCs through the CCR9\/CCL25 axis and therefore promote liver fibrosis. CCR9 antagonism might be a novel therapeutic target for liver fibrosis. (HEPATOLOGY 2013;)<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.26351","type":"journal-article","created":{"date-parts":[[2013,3,5]],"date-time":"2013-03-05T06:35:38Z","timestamp":1362465338000},"page":"337-350","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":86,"title":["C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice"],"prefix":"10.1097","volume":"58","author":[{"given":"Po-sung","family":"Chu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiro","family":"Nakamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotoshi","family":"Ebinuma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Usui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keita","family":"Saeki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsuhiro","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Mikami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuo","family":"Sugiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kengo","family":"Tomita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Kanai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetsugu","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshifumi","family":"Hibi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-37-20241201","doi-asserted-by":"crossref","first-page":"16461654","DOI":"10.1056\/NEJMra035021","article-title":"Management of cirrhosis and ascites.","volume":"350","author":"Gines","year":"2004","journal-title":"N Engl J Med"},{"issue":"Suppl 1","key":"R2-37-20241201","first-page":"S38S53","article-title":"Liver fibrosis from bench to bedside.","volume":"38","author":"Friedman","year":"2003","journal-title":"J Hepatol"},{"key":"R3-37-20241201","doi-asserted-by":"crossref","first-page":"209218","DOI":"10.1172\/JCI24282","article-title":"Liver fibrosis.","volume":"115","author":"Bataller","year":"2005","journal-title":"J Clin Invest"},{"key":"R4-37-20241201","doi-asserted-by":"crossref","first-page":"16641668","DOI":"10.1002\/hep.23338","article-title":"Chemokine (CC motif) receptors in fibrogenesis and hepatic regeneration following acute and chronic liver disease.","volume":"50","author":"Ramm","year":"2009","journal-title":"HEPATOLOGY"},{"key":"R5-37-20241201","doi-asserted-by":"crossref","first-page":"125172","DOI":"10.1152\/physrev.00013.2007","article-title":"Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver.","volume":"88","author":"Friedman","year":"2008","journal-title":"Physiol Rev"},{"key":"R6-37-20241201","doi-asserted-by":"crossref","first-page":"261274","DOI":"10.1002\/hep.22950","article-title":"Hepatic recruitment of the inflammatory Gr1 monocyte subset upon liver injury promotes hepatic fibrosis.","volume":"50","author":"Karlmark","year":"2009","journal-title":"HEPATOLOGY"},{"key":"R7-37-20241201","doi-asserted-by":"crossref","first-page":"138146","DOI":"10.1053\/j.gastro.2004.10.005","article-title":"Suppression of macrophage infiltration inhibits activation of hepatic stellate cells and liver fibrogenesis in rats.","volume":"128","author":"Imamura","year":"2005","journal-title":"Gastroenterology"},{"key":"R8-37-20241201","doi-asserted-by":"crossref","first-page":"5665","DOI":"10.1172\/JCI200522675","article-title":"Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair.","volume":"115","author":"Duffield","year":"2005","journal-title":"J Clin Invest"},{"key":"R9-37-20241201","doi-asserted-by":"crossref","first-page":"185197","DOI":"10.1002\/hep.22952","article-title":"CCR2 promotes hepatic fibrosis in mice.","volume":"50","author":"Seki","year":"2009","journal-title":"HEPATOLOGY"},{"key":"R10-37-20241201","first-page":"18581870","article-title":"CCR1 and CCR5 promote hepatic fibrosis in mice.","volume":"119","author":"Seki","year":"2009","journal-title":"J Clin Invest"},{"key":"R11-37-20241201","doi-asserted-by":"crossref","first-page":"898909","DOI":"10.1002\/hep.24764","article-title":"Hepatic macrophage migration and differentiation critical for liver fibrosis is mediated by the chemokine receptor CC motif chemokine receptor 8 in mice.","volume":"55","author":"Heymann","year":"2012","journal-title":"HEPATOLOGY"},{"key":"R12-37-20241201","doi-asserted-by":"crossref","first-page":"13901400","DOI":"10.1002\/hep.23795","article-title":"CX3CL1CX3CR1 interaction prevents carbon tetrachlorideinduced liver inflammation and fibrosis in mice.","volume":"52","author":"Aoyama","year":"2010","journal-title":"HEPATOLOGY"},{"key":"R13-37-20241201","doi-asserted-by":"crossref","first-page":"17691782","DOI":"10.1002\/hep.23894","article-title":"The fractalkine receptor CX(3)CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes.","volume":"52","author":"Karlmark","year":"2010","journal-title":"HEPATOLOGY"},{"key":"R14-37-20241201","doi-asserted-by":"crossref","first-page":"682690","DOI":"10.1038\/nrgastro.2010.168","article-title":"Functional role of chemokines in liver disease models.","volume":"7","author":"Sahin","year":"2010","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"R15-37-20241201","doi-asserted-by":"crossref","first-page":"291301","DOI":"10.1016\/S1074-7613(00)80531-2","article-title":"TECK: a novel CC chemokine specifically expressed by thymic dendritic cells and potentially involved in T cell development.","volume":"7","author":"Vicari","year":"1997","journal-title":"Immunity"},{"key":"R16-37-20241201","doi-asserted-by":"crossref","first-page":"56715675","DOI":"10.4049\/jimmunol.162.10.5671","article-title":"Cutting edge: identification of the orphan chemokine receptor GPR96 as CCR9, the receptor for the chemokine TECK.","volume":"162","author":"Zaballos","year":"1999","journal-title":"J Immunol"},{"key":"R17-37-20241201","doi-asserted-by":"crossref","first-page":"466476","DOI":"10.1111\/j.1365-2567.2009.03043.x","article-title":"Inverse relationship between dendritic cell CCR9 expression and maturation state.","volume":"127","author":"Drakes","year":"2009","journal-title":"Immunology"},{"key":"R18-37-20241201","doi-asserted-by":"crossref","first-page":"12411256","DOI":"10.1084\/jem.190.9.1241","article-title":"Human G proteincoupled receptor GPR96CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosal lymphocytes, and thymocytes and is required for thymusexpressed chemokinemediated chemotaxis.","volume":"190","author":"Zabel","year":"1999","journal-title":"J Exp Med"},{"key":"R19-37-20241201","doi-asserted-by":"crossref","first-page":"63476352","DOI":"10.1073\/pnas.0609180104","article-title":"CCR9 is a homing receptor for plasmacytoid dendritic cells to the small intestine.","volume":"104","author":"Wendland","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R20-37-20241201","doi-asserted-by":"crossref","first-page":"12531260","DOI":"10.1038\/ni.1658","article-title":"CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graftversushost disease.","volume":"9","author":"Hadeiba","year":"2008","journal-title":"Nat Immunol"},{"key":"R21-37-20241201","doi-asserted-by":"crossref","first-page":"32933300","DOI":"10.4049\/jimmunol.178.5.3293","article-title":"Phenotype and effector function of CC chemokine receptor 9expressing lymphocytes in small intestinal Crohns disease.","volume":"178","author":"Saruta","year":"2007","journal-title":"J Immunol"},{"key":"R22-37-20241201","doi-asserted-by":"crossref","first-page":"15111517","DOI":"10.1084\/jem.20041035","article-title":"Hepatic endothelial CCL25 mediates the recruitment of CCR9 guthoming lymphocytes to the liver in primary sclerosing cholangitis.","volume":"200","author":"Eksteen","year":"2004","journal-title":"J Exp Med"},{"key":"R23-37-20241201","doi-asserted-by":"crossref","first-page":"366376","DOI":"10.1053\/j.gastro.2011.10.039","article-title":"CCR9 macrophages are required for acute liver inflammation in mouse models of hepatitis.","volume":"142","author":"Nakamoto","year":"2012","journal-title":"Gastroenterology"},{"key":"R24-37-20241201","doi-asserted-by":"crossref","first-page":"28112819","DOI":"10.4049\/jimmunol.168.6.2811","article-title":"A role for CCR9 in T lymphocyte development and migration.","volume":"168","author":"Uehara","year":"2002","journal-title":"J Immunol"},{"key":"R25-37-20241201","first-page":"32133225","article-title":"In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNFalpha.","volume":"119","author":"Connolly","year":"2009","journal-title":"J Clin Invest"},{"key":"R26-37-20241201","doi-asserted-by":"crossref","first-page":"744749","DOI":"10.1016\/j.bbrc.2010.08.012","article-title":"MyD88dependent pathway accelerates the liver damage of Concanavalin Ainduced hepatitis.","volume":"399","author":"Ojiro","year":"2010","journal-title":"Biochem Biophys Res Commun"},{"key":"R27-37-20241201","doi-asserted-by":"crossref","first-page":"24092422","DOI":"10.1002\/eji.201040379","article-title":"Competition between colitogenic Th1 and Th17 cells contributes to the amelioration of colitis.","volume":"40","author":"Mikami","year":"2010","journal-title":"Eur J Immunol"},{"key":"R28-37-20241201","first-page":"305314","article-title":"Acetaminopheninduced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome.","volume":"119","author":"Imaeda","year":"2009","journal-title":"J Clin Invest"},{"key":"R29-37-20241201","doi-asserted-by":"crossref","first-page":"609618","DOI":"10.1016\/j.imbio.2006.05.025","article-title":"Migratory fate and differentiation of blood monocyte subsets.","volume":"211","author":"Tacke","year":"2006","journal-title":"Immunobiology"},{"key":"R30-37-20241201","doi-asserted-by":"crossref","first-page":"319327","DOI":"10.1002\/hep.24388","article-title":"Critical role of tumor necrosis factor receptor 1, but not 2, in hepatic stellate cell proliferation, extracellular matrix remodeling, and liver fibrogenesis.","volume":"54","author":"Tarrats","year":"2011","journal-title":"HEPATOLOGY"},{"key":"R31-37-20241201","doi-asserted-by":"crossref","first-page":"90104","DOI":"10.1111\/j.0105-2896.2009.00876.x","article-title":"Differentiation and function of mouse monocytederived dendritic cells in steady state and inflammation.","volume":"234","author":"Dominguez","year":"2010","journal-title":"Immunol Rev"},{"key":"R32-37-20241201","doi-asserted-by":"crossref","first-page":"2349623505","DOI":"10.1074\/jbc.M110.117481","article-title":"Angiotensinconverting enzyme inhibition downregulates the proatherogenic chemokine receptor 9 (CCR9)chemokine ligand 25 (CCL25) axis.","volume":"285","author":"Abd Alla","year":"2010","journal-title":"J Biol Chem"},{"key":"R33-37-20241201","doi-asserted-by":"crossref","first-page":"R161","DOI":"10.1186\/ar3120","article-title":"Monocytesmacrophages express chemokine receptor CCR9 in rheumatoid arthritis and CCL25 stimulates their differentiation.","volume":"12","author":"Schmutz","year":"2010","journal-title":"Arthritis Res Ther"},{"key":"R34-37-20241201","doi-asserted-by":"crossref","first-page":"850857","DOI":"10.1182\/blood.V97.4.850","article-title":"Expression of CCR9 betachemokine receptor is modulated in thymocyte differentiation and is selectively maintained in CD8() T cells from secondary lymphoid organs.","volume":"97","author":"Carramolino","year":"2001","journal-title":"Blood"},{"key":"R35-37-20241201","doi-asserted-by":"crossref","first-page":"870882","DOI":"10.1053\/j.gastro.2004.04.062","article-title":"Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin10 from hepatocytes.","volume":"127","author":"Safadi","year":"2004","journal-title":"Gastroenterology"},{"key":"R36-37-20241201","doi-asserted-by":"crossref","first-page":"295303","DOI":"10.1016\/j.jhep.2006.09.014","article-title":"IFNgamma abrogates profibrogenic TGFbeta signaling in liver by targeting expression of inhibitory and receptor Smads.","volume":"46","author":"Weng","year":"2007","journal-title":"J Hepatol"},{"key":"R37-37-20241201","doi-asserted-by":"crossref","first-page":"586596","DOI":"10.1002\/hep.24395","article-title":"Novel engineered targeted interferongamma blocks hepatic fibrogenesis in mice.","volume":"54","author":"Bansal","year":"2011","journal-title":"HEPATOLOGY"},{"key":"R38-37-20241201","doi-asserted-by":"crossref","first-page":"26902694","DOI":"10.4049\/jimmunol.179.5.2690","article-title":"Cutting edge: Peyers patch plasmacytoid dendritic cells (pDCs) produce low levels of type I interferons: possible role for IL10, TGFbeta, and prostaglandin E2 in conditioning a unique mucosal pDC phenotype.","volume":"179","author":"Contractor","year":"2007","journal-title":"J Immunol"},{"key":"R39-37-20241201","doi-asserted-by":"crossref","first-page":"29512956","DOI":"10.4049\/jimmunol.180.5.2951","article-title":"Splenic stromal microenvironment negatively regulates virusactivated plasmacytoid dendritic cells through TGFbeta.","volume":"180","author":"Li","year":"2008","journal-title":"J Immunol"},{"key":"R40-37-20241201","doi-asserted-by":"crossref","first-page":"527538","DOI":"10.1016\/j.immuni.2004.08.011","article-title":"Retinoic acid imprints guthoming specificity on T cells.","volume":"21","author":"Iwata","year":"2004","journal-title":"Immunity"},{"key":"R41-37-20241201","doi-asserted-by":"crossref","first-page":"117129","DOI":"10.1016\/j.immuni.2006.11.011","article-title":"Ito cells are liverresident antigenpresenting cells for activating T cell responses.","volume":"26","author":"Winau","year":"2007","journal-title":"Immunity"},{"key":"R42-37-20241201","doi-asserted-by":"crossref","first-page":"320329","DOI":"10.1053\/j.gastro.2009.02.046","article-title":"Gut homing receptors on CD8 T cells are retinoic acid dependent and not maintained by liver dendritic or stellate cells.","volume":"137","author":"Eksteen","year":"2009","journal-title":"Gastroenterology"},{"key":"R43-37-20241201","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1007\/s10787-011-0104-6","article-title":"Targeting leukocyte migration and adhesion in Crohns disease and ulcerative colitis.","volume":"20","author":"Thomas","year":"2012","journal-title":"Inflammopharmacology"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.26351","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201307000-00037","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T14:13:21Z","timestamp":1733062401000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201307000-00037"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,7]]},"references-count":43,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2013]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.26351","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2013,7]]}}}