{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:45:26Z","timestamp":1791276326972,"version":"4.1.0"},"reference-count":45,"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":2253,"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":[[2009,7]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Chemokines and chemokine receptors contribute to the migration of hepatic stellate cells (HSCs) and Kupffer cells, two key cell types in fibrogenesis. Here, we investigate the role of CCR2, the receptor for monocyte chemoattractant protein (MCP)-1, MCP-2, and MCP-3, in hepatic fibrosis. Hepatic CCR2, MCP-1, MCP-2, and MCP-3 messenger RNA expression was increased after bile duct ligation (BDL). Both Kupffer cells and HSCs, but not hepatocytes, expressed CCR2. BDL- and CCl\n                      <jats:sub>4<\/jats:sub>\n                      -induced fibrosis was markedly reduced in CCR2\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice as assessed through collagen deposition, \u03b1-smooth muscle actin expression, and hepatic hydroxyproline content. We generated CCR2 chimeric mice by the combination of clodronate, irradiation, and bone marrow (BM) transplantation allowing full reconstitution of Kupffer cells, but not HSCs, with BM cells. Chimeric mice containing wild-type BM displayed increased macrophage recruitment, whereas chimeric mice containing CCR2\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      BM showed less macrophage recruitment at 5 days after BDL. Although CCR2 expressed in the BM enhanced macrophage recruitment in early phases of injury, CCR2 expression on resident liver cells including HSCs, but not on the BM, was required for fibrogenic responses in chronic fibrosis models.\n                      <jats:italic toggle=\"yes\">In vitro<\/jats:italic>\n                      experiments demonstrated that HSCs deficient in CCR2\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      or its downstream mediator p47phox\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      did not display extracellular signal-regulated kinase and AKT phosphorylation, chemotaxis, or reactive oxygen species production in response to MCP-1, MCP-2, and MCP-3.\n                      <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                      Our results indicate that CCR2 promotes HSC chemotaxis and the development of hepatic fibrosis. (Hepatology 2009.)\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.22952","type":"journal-article","created":{"date-parts":[[2009,3,16]],"date-time":"2009-03-16T10:38:30Z","timestamp":1237199910000},"page":"185-197","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":377,"title":["CCR2 promotes hepatic fibrosis in mice #"],"prefix":"10.1097","volume":"50","author":[{"given":"Ekihiro","family":"Seki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuele","family":"de Minicis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayaka","family":"Inokuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kojiro","family":"Taura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsumi","family":"Miyai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nico","family":"van Rooijen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert F.","family":"Schwabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Brenner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-21-20241201","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1172\/JCI24282","article-title":"Liver fibrosis.","volume":"115","author":"Bataller","year":"2005","journal-title":"J Clin Invest"},{"key":"R2-21-20241201","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1074\/jbc.275.4.2247","article-title":"Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury.","volume":"275","author":"Friedman","year":"2000","journal-title":"J Biol Chem"},{"key":"R3-21-20241201","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1053\/j.gastro.2008.03.003","article-title":"Mechanisms of hepatic fibrogenesis.","volume":"134","author":"Friedman","year":"2008","journal-title":"Gastroenterology"},{"key":"R4-21-20241201","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/nri1703","article-title":"NFkappaB: linking inflammation and immunity to cancer development and progression.","volume":"5","author":"Karin","year":"2005","journal-title":"Nat Rev Immunol"},{"key":"R5-21-20241201","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.1172\/JCI114362","article-title":"Activation of cultured rat hepatic lipocytes by Kupffer cell conditioned medium. Direct enhancement of matrix synthesis and stimulation of cell proliferation via induction of plateletderived growth factor receptors.","volume":"84","author":"Friedman","year":"1989","journal-title":"J Clin Invest"},{"key":"R6-21-20241201","doi-asserted-by":"crossref","first-page":"56","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":"R7-21-20241201","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1038\/nm1663","article-title":"TLR4 enhances TGFbeta signaling and hepatic fibrosis.","volume":"13","author":"Seki","year":"2007","journal-title":"Nat Med"},{"key":"R8-21-20241201","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nri1776","article-title":"Chemokines: more than just road signs.","volume":"6","author":"Bachmann","year":"2006","journal-title":"Nat Rev Immunol"},{"key":"R9-21-20241201","doi-asserted-by":"crossref","first-page":"3664","DOI":"10.1002\/eji.200425294","article-title":"CC chemokine receptor 2 regulates leukocyte recruitment and IL10 production during acute polymicrobial sepsis.","volume":"34","author":"Feterowski","year":"2004","journal-title":"Eur J Immunol"},{"key":"R10-21-20241201","doi-asserted-by":"crossref","first-page":"7647","DOI":"10.4049\/jimmunol.172.12.7647","article-title":"CCR2dependent trafficking of F480dim macrophages and CD11cdimintermediate dendritic cells is crucial for T cell recruitment to lungs infected with Mycobacterium tuberculosis.","volume":"172","author":"Peters","year":"2004","journal-title":"J Immunol"},{"key":"R11-21-20241201","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1172\/JCI200420126","article-title":"Experimental arthritis in CC chemokine receptor 2null mice closely mimics severe human rheumatoid arthritis.","volume":"113","author":"Quinones","year":"2004","journal-title":"J Clin Invest"},{"key":"R12-21-20241201","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0165-5728(02)00147-9","article-title":"Upregulation of monocyte chemotactic protein1 and CC chemokine receptor 2 in the central nervous system is closely associated with relapse of autoimmune encephalomyelitis in Lewis rats.","volume":"128","author":"Jee","year":"2002","journal-title":"J Neuroimmunol"},{"key":"R13-21-20241201","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1097\/00041433-200404000-00007","article-title":"The role of chemokines in atherosclerosis: recent evidence from experimental models and population genetics.","volume":"15","author":"Bursill","year":"2004","journal-title":"Curr Opin Lipidol"},{"key":"R14-21-20241201","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1189\/jlb.0305127","article-title":"MCP1CCR2dependent loop for fibrogenesis in human peripheral CD14positive monocytes.","volume":"79","author":"Sakai","year":"2006","journal-title":"J Leukoc Biol"},{"key":"R15-21-20241201","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1172\/JCI29919","article-title":"Critical roles for CCR2 and MCP3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites.","volume":"117","author":"Tsou","year":"2007","journal-title":"J Clin Invest"},{"key":"R16-21-20241201","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1172\/JCI24335","article-title":"CCR2 modulates inflammatory and metabolic effects of highfat feeding.","volume":"116","author":"Weisberg","year":"2006","journal-title":"J Clin Invest"},{"key":"R17-21-20241201","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.cyto.2003.08.003","article-title":"CCchemokine receptor 2 required for bleomycininduced pulmonary fibrosis.","volume":"24","author":"GharaeeKermani","year":"2003","journal-title":"Cytokine"},{"key":"R18-21-20241201","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1002\/path.1667","article-title":"CC chemokine receptor 2 (CCR2) deficiency improves bleomycininduced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophagederived matrix metalloproteinases.","volume":"204","author":"Okuma","year":"2004","journal-title":"J Pathol"},{"key":"R19-21-20241201","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/S0002-9440(10)63292-0","article-title":"Blockade of CCR2 ameliorates progressive fibrosis in kidney.","volume":"165","author":"Kitagawa","year":"2004","journal-title":"Am J Pathol"},{"key":"R20-21-20241201","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.jhep.2006.09.007","article-title":"Prevention of severe toxic liver injury and oxidative stress in MCP1deficient mice.","volume":"46","author":"Zamara","year":"2007","journal-title":"J Hepatol"},{"key":"R21-21-20241201","doi-asserted-by":"crossref","first-page":"138","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":"R22-21-20241201","first-page":"423","article-title":"Increased expression of monocyte chemotactic protein1 during active hepatic fibrogenesis: correlation with monocyte infiltration.","volume":"152","author":"Marra","year":"1998","journal-title":"Am J Pathol"},{"key":"R23-21-20241201","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1002\/hep.21268","article-title":"Loss of MMP 13 attenuates murine hepatic injury and fibrosis during cholestasis.","volume":"44","author":"Uchinami","year":"2006","journal-title":"HEPATOLOGY"},{"key":"R24-21-20241201","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.jhep.2006.04.014","article-title":"Bone marrowderived fibrocytes participate in pathogenesis of liver fibrosis.","volume":"45","author":"Kisseleva","year":"2006","journal-title":"J Hepatol"},{"key":"R25-21-20241201","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1182\/blood.V90.3.986","article-title":"Kinetics of central nervous system microglial and macrophage engraftment: analysis using a transgenic bone marrow transplantation model.","volume":"90","author":"Kennedy","year":"1997","journal-title":"Blood"},{"key":"R26-21-20241201","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/S0167-7799(97)01019-6","article-title":"Transient suppression of macrophage functions by liposomeencapsulated drugs.","volume":"15","author":"van Rooijen","year":"1997","journal-title":"Trends Biotechnol"},{"key":"R27-21-20241201","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1053\/j.gastro.2007.02.033","article-title":"Gene expression profiles during hepatic stellate cell activation in culture and in vivo.","volume":"132","author":"De Minicis","year":"2007","journal-title":"Gastroenterology"},{"key":"R28-21-20241201","doi-asserted-by":"crossref","first-page":"2651","DOI":"10.4049\/jimmunol.166.4.2651","article-title":"Lipopolysaccharideinduced IL18 secretion from murine Kupffer cells independently of myeloid differentiation factor 88 that is critically involved in induction of production of IL12 and IL1beta.","volume":"166","author":"Seki","year":"2001","journal-title":"J Immunol"},{"key":"R29-21-20241201","doi-asserted-by":"crossref","first-page":"3863","DOI":"10.4049\/jimmunol.169.7.3863","article-title":"Critical roles of myeloid differentiation factor 88dependent proinflammatory cytokine release in early phase clearance of Listeria monocytogenes in mice.","volume":"169","author":"Seki","year":"2002","journal-title":"J Immunol"},{"key":"R30-21-20241201","doi-asserted-by":"crossref","first-page":"G949","DOI":"10.1152\/ajpgi.00215.2003","article-title":"Human hepatic stellate cells express CCR5 and RANTES to induce proliferation and migration.","volume":"285","author":"Schwabe","year":"2003","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R31-21-20241201","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1172\/JCI18212","article-title":"NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis.","volume":"112","author":"Bataller","year":"2003","journal-title":"J Clin Invest"},{"key":"R32-21-20241201","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1002\/1096-9896(2000)9999:9999<::AID-PATH725>3.0.CO;2-P","article-title":"Monocyte chemotactic protein1, 2, and 3 are distinctively expressed in portal tracts and granulomata in primary biliary cirrhosis: implications for pathogenesis.","volume":"193","author":"Tsuneyama","year":"2001","journal-title":"J Pathol"},{"key":"R33-21-20241201","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1172\/JCI30542","article-title":"Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ.","volume":"117","author":"Iredale","year":"2007","journal-title":"J Clin Invest"},{"key":"R34-21-20241201","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1053\/jhep.2001.22761","article-title":"Agonistspecific regulation of monocyte chemoattractant protein1 expression by cyclooxygenase metabolites in hepatic stellate cells.","volume":"33","author":"Efsen","year":"2001","journal-title":"HEPATOLOGY"},{"key":"R35-21-20241201","doi-asserted-by":"crossref","first-page":"G765","DOI":"10.1152\/ajpgi.00308.2005","article-title":"Secretion of MCP1CCL2 by bile duct epithelia induces myofibroblastic transdifferentiation of portal fibroblasts.","volume":"290","author":"Kruglov","year":"2006","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R36-21-20241201","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1002\/hep.22637","article-title":"Fibrogenesis in pediatric cholestatic liver disease: role of taurocholate and hepatocytederived monocyte chemotaxis protein1 in hepatic stellate cell recruitment.","volume":"49","author":"Ramm","year":"2009","journal-title":"HEPATOLOGY"},{"key":"R37-21-20241201","doi-asserted-by":"crossref","first-page":"G518","DOI":"10.1152\/ajpgi.00024.2006","article-title":"Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis.","volume":"292","author":"Brun","year":"2007","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R38-21-20241201","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1053\/jhep.2002.33162","article-title":"Role of CCR2 in macrophage migration into the liver during acetaminopheninduced hepatotoxicity in the mouse.","volume":"35","author":"Dambach","year":"2002","journal-title":"HEPATOLOGY"},{"key":"R39-21-20241201","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1016\/S0002-9440(10)64995-4","article-title":"Exaggerated hepatic injury due to acetaminophen challenge in mice lacking CC chemokine receptor 2.","volume":"156","author":"Hogaboam","year":"2000","journal-title":"Am J Pathol"},{"key":"R40-21-20241201","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1172\/JCI28549","article-title":"Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques.","volume":"117","author":"Tacke","year":"2007","journal-title":"J Clin Invest"},{"key":"R41-21-20241201","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1038\/ni1309","article-title":"Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2.","volume":"7","author":"Serbina","year":"2006","journal-title":"Nat Immunol"},{"key":"R42-21-20241201","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1002\/hep.510290107","article-title":"Monocyte chemotactic protein1 as a chemoattractant for human hepatic stellate cells.","volume":"29","author":"Marra","year":"1999","journal-title":"HEPATOLOGY"},{"key":"R43-21-20241201","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1002\/hep.22404","article-title":"Monocyte chemoattractant protein1 secreted by adipose tissue induces direct lipid accumulation in hepatocytes.","volume":"48","author":"Clement","year":"2008","journal-title":"HEPATOLOGY"},{"key":"R44-21-20241201","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1007\/s11373-005-1703-2","article-title":"Reactive oxygen species and ERK 12 mediate monocyte chemotactic protein1stimulated smooth muscle cell migration.","volume":"12","author":"Lo","year":"2005","journal-title":"J Biomed Sci"},{"key":"R45-21-20241201","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/S0735-1097(00)01110-4","article-title":"Interaction between chemokines and oxidative stress: possible pathogenic role in acute coronary syndromes.","volume":"37","author":"Aukrust","year":"2001","journal-title":"J Am Coll Cardiol"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.22952","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-200907000-00021","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T08:44:04Z","timestamp":1733042644000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-200907000-00021"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,7]]},"references-count":45,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2009]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.22952","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1159721.621123","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.1159721.623015","asserted-by":"object"}]},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2009,7]]}}}