{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T04:41:26Z","timestamp":1789965686204,"version":"4.0.1"},"reference-count":35,"publisher":"Portland Press Ltd.","issue":"16","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,8,15]]},"abstract":"<jats:p>Background and aims: TLR9 deletion protects against steatohepatitis due to choline\u2013amino acid depletion and high-fat diet. We measured TLR9 in human non-alcoholic steatohepatitis (NASH) livers, and tested whether TLR9 mediates inflammatory recruitment in three murine models of non-alcoholic fatty liver disease (NAFLD). Methods: We assayed TLR mRNA in liver biopsies from bariatric surgery patients. Wild-type (Wt), appetite-dysregulated Alms1 mutant (foz\/foz), Tlr9\u2212\/\u2212, and Tlr9\u2212\/\u2212.foz\/foz C57BL6\/J mice and bone marrow (BM) chimeras were fed 0.2% cholesterol, high-fat, high sucrose (atherogenic[Ath]) diet or chow, and NAFLD activity score (NAS)\/NASH pathology, macrophage\/neutrophil infiltration, cytokines\/chemokines, and cell death markers measured in livers. Results: Hepatic TLR9 and TLR4 mRNA were increased in human NASH but not simple steatosis, and in Ath-fed foz\/foz mice with metabolic syndrome-related NASH. Ath-fed Tlr9\u2212\/\u2212 mice showed simple steatosis and less Th1 cytokines than Wt. Tlr9\u2212\/\u2212.foz\/foz mice were obese and diabetic, but necroinflammatory changes were less severe than Tlr9+\/+.foz\/foz mice. TLR9-expressing myeloid cells were critical for Th1 cytokine production in BM chimeras. BM macrophages from Tlr9\u2212\/\u2212 mice showed M2 polarization, were resistant to M1 activation by necrotic hepatocytes\/other pro-inflammatory triggers, and provoked less neutrophil chemotaxis than Wt. Livers from Ath-fed Tlr9\u2212\/\u2212 mice appeared to exhibit more markers of necroptosis [receptor interacting protein kinase (RIP)-1, RIP-3, and mixed lineage kinase domain-like protein (MLKL)] than Wt, and \u223c25% showed portal foci of mononuclear cells unrelated to NASH pathology. Conclusion: Our novel clinical data and studies in overnutrition models, including those with diabetes and metabolic syndrome, clarify TLR9 as a pro-inflammatory trigger in NASH. This response is mediated via M1-macrophages and neutrophil chemotaxis.<\/jats:p>","DOI":"10.1042\/cs20160838","type":"journal-article","created":{"date-parts":[[2017,7,7]],"date-time":"2017-07-07T20:10:12Z","timestamp":1499458212000},"page":"2145-2159","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":80,"title":["TLR9 is up-regulated in human and murine NASH: pivotal role in inflammatory recruitment and cell survival"],"prefix":"10.1042","volume":"131","author":[{"given":"Auvro\u00a0R.","family":"Mridha","sequence":"first","affiliation":[{"name":"Liver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fahrettin","family":"Haczeyni","sequence":"additional","affiliation":[{"name":"Liver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew\u00a0M.","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Washington, Seattle, WA, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.\u00a0Geoffrey","family":"Haigh","sequence":"additional","affiliation":[{"name":"Department of Medicine\/Gastroenterology, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WA, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George\u00a0N.","family":"Ioannou","sequence":"additional","affiliation":[{"name":"Department of Medicine\/Gastroenterology, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WA, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Barn","sequence":"additional","affiliation":[{"name":"Liver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hussam","family":"Ajamieh","sequence":"additional","affiliation":[{"name":"Liver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon","family":"Adams","sequence":"additional","affiliation":[{"name":"School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey\u00a0M.","family":"Hamdorf","sequence":"additional","affiliation":[{"name":"School of Surgery, University of Western Australia, Perth, WA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narci\u00a0C.","family":"Teoh","sequence":"additional","affiliation":[{"name":"Liver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey\u00a0C.","family":"Farrell","sequence":"additional","affiliation":[{"name":"Liver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2017,7,24]]},"reference":[{"key":"2021113010521941500_B1","doi-asserted-by":"crossref","DOI":"10.1002\/9781118556153","volume-title":"Non-Alcoholic Fatty Liver Disease: A Practical Guide","author":"Farrell","year":"2013"},{"key":"2021113010521941500_B2","doi-asserted-by":"crossref","first-page":"149","DOI":"10.5009\/gnl.2012.6.2.149","article-title":"NASH is an inflammatory disorder: pathogenic, prognostic and therapeutic implications","volume":"6","author":"Farrell","year":"2012","journal-title":"Gut Liver"},{"key":"2021113010521941500_B3","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"2021113010521941500_B4","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1053\/j.gastro.2014.07.018","article-title":"Cell death and cell death responses in liver disease: mechanisms and clinical relevance","volume":"147","author":"Luedde","year":"2014","journal-title":"Gastroenterology"},{"key":"2021113010521941500_B5","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1172\/JCI83885","article-title":"Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9","volume":"126","author":"Garcia-Martinez","year":"2016","journal-title":"J. Clin. Invest"},{"key":"2021113010521941500_B6","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1053\/j.gastro.2012.09.008","article-title":"Sterile inflammation in the liver","volume":"143","author":"Kubes","year":"2012","journal-title":"Gastroenterology"},{"key":"2021113010521941500_B7","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1053\/j.gastro.2010.05.018","article-title":"Innate immunity and steatohepatitis: a critical role of another toll (TLR-9)","volume":"139","author":"Gao","year":"2010","journal-title":"Gastroenterology"},{"key":"2021113010521941500_B8","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1002\/hep.22399","article-title":"Beyond insulin resistance: Innate immunity in nonalcoholic steatohepatitis","volume":"48","author":"Maher","year":"2008","journal-title":"Hepatology"},{"key":"2021113010521941500_B9","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.jhep.2007.04.019","article-title":"Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis","volume":"47","author":"Rivera","year":"2007","journal-title":"J. Hepatol."},{"key":"2021113010521941500_B10","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1053\/j.gastro.2006.01.038","article-title":"Toll-like receptor signaling in the liver","volume":"130","author":"Schwabe","year":"2006","journal-title":"Gastroenterology"},{"key":"2021113010521941500_B11","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1053\/jhep.2001.29628","article-title":"Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients","volume":"34","author":"Crespo","year":"2001","journal-title":"Hepatology"},{"key":"2021113010521941500_B12","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/labinvest.2014.3","article-title":"Increased expression of c-Jun in nonalcoholic fatty liver disease","volume":"94","author":"Dorn","year":"2014","journal-title":"Lab. Invest."},{"key":"2021113010521941500_B13","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1053\/j.gastro.2005.09.004","article-title":"NF-kappaB activation, rather than TNF, mediates hepatic inflammation in a murine dietary model of steatohepatitis","volume":"129","author":"Dela Pena","year":"2005","journal-title":"Gastroenterology"},{"key":"2021113010521941500_B14","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1053\/j.gastro.2009.06.045","article-title":"c-Jun N-terminal kinase-1 from hematopoietic cells mediates progression from hepatic steatosis to steatohepatitis and fibrosis in mice","volume":"137","author":"Kodama","year":"2009","journal-title":"Gastroenterology"},{"key":"2021113010521941500_B15","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1002\/hep.20999","article-title":"JNK1 but not JNK2 promotes the development of steatohepatitis in mice","volume":"43","author":"Schattenberg","year":"2006","journal-title":"Hepatology"},{"key":"2021113010521941500_B16","doi-asserted-by":"crossref","first-page":"12093","DOI":"10.1074\/jbc.M510660200","article-title":"Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis","volume":"281","author":"Malhi","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2021113010521941500_B17","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1053\/j.gastro.2012.06.004","article-title":"A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches","volume":"143","author":"Seki","year":"2012","journal-title":"Gastroenterology"},{"key":"2021113010521941500_B18","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1016\/j.jhep.2014.07.024","article-title":"Hepatocyte free cholesterol lipotoxicity results from JNK1-mediated mitochondrial injury and is HMGB1 and TLR4-dependent","volume":"61","author":"Gan","year":"2014","journal-title":"J. Hepatol."},{"key":"2021113010521941500_B19","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1002\/hep.24552","article-title":"Nuclear factor high-mobility group box1 mediating the activation of Toll-like receptor 4 signaling in hepatocytes in the early stage of nonalcoholic fatty liver disease in mice","volume":"54","author":"Li","year":"2011","journal-title":"Hepatology"},{"key":"2021113010521941500_B20","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1053\/j.gastro.2010.03.052","article-title":"Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice","volume":"139","author":"Miura","year":"2010","journal-title":"Gastroenterology"},{"key":"2021113010521941500_B21","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1111\/jgh.12112","article-title":"Cross talk between toll-like receptor-4 signaling and angiotensin-II in liver fibrosis development in the rat model of non-alcoholic steatohepatitis","volume":"28","author":"Shirai","year":"2013","journal-title":"J. Gastroenterol. Hepatol."},{"key":"2021113010521941500_B22","first-page":"12442","article-title":"Expression of toll-like receptors 1-5 but not TLR 6-10 is elevated in livers of patients with non-alcoholic fatty liver disease","volume":"18","author":"Kanuri","year":"2013","journal-title":"Liver Int."},{"key":"2021113010521941500_B23","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1111\/j.1440-1746.2009.05996.x","article-title":"Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice","volume":"24","author":"Larter","year":"2009","journal-title":"J. Gastroenterol. Hepatol."},{"key":"2021113010521941500_B24","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1053\/j.gastro.2011.06.040","article-title":"Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis","volume":"141","author":"Van Rooyen","year":"2011","journal-title":"Gastroenterology"},{"key":"2021113010521941500_B25","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1111\/liv.12335","article-title":"Strain dependence of diet-induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype","volume":"34","author":"Farrell","year":"2014","journal-title":"Liver Int."},{"key":"2021113010521941500_B26","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1007\/BF00316069","article-title":"Quantitation of adipose conversion and triglycerides by staining intracytoplasmic lipids with Oil red O","volume":"97","author":"Ramirez-Zacarias","year":"1992","journal-title":"Histochemistry"},{"key":"2021113010521941500_B27","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/0022-1759(80)90036-8","article-title":"Optimal conditions for simultaneous purification of mononuclear and polymorphonuclear leucocytes from human blood by the Hypaque-Ficoll method","volume":"36","author":"Ferrante","year":"1980","journal-title":"J. Immunol. Meth."},{"key":"2021113010521941500_B28","doi-asserted-by":"publisher","first-page":"e745","DOI":"10.3791\/745","article-title":"Neutrophil isolation protocol","author":"Oh","year":"2008","journal-title":"J. Vis. Exp."},{"key":"2021113010521941500_B29","doi-asserted-by":"publisher","first-page":"e104306","DOI":"10.1371\/journal.pone.0104376","article-title":"Microparticles mediate hepatic ischemia-reperfusion injury and are the targets of Diannexin (ASP8597)","volume":"9","author":"Teoh","year":"2014","journal-title":"PLoS One"},{"key":"2021113010521941500_B30","doi-asserted-by":"crossref","first-page":"G583","DOI":"10.1152\/ajpgi.00422.2005","article-title":"Mechanisms of Liver Injury. I. TNF-alpha-induced liver injury: role of IKK, JNK, and ROS pathways","volume":"290","author":"Schwabe","year":"2006","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"2021113010521941500_B31","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1002\/hep.23122","article-title":"Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice","volume":"50","author":"Spruss","year":"2009","journal-title":"Hepatology"},{"key":"2021113010521941500_B32","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1038\/nm1663","article-title":"TLR4 enhances TGF-beta signaling and hepatic fibrosis","volume":"13","author":"Seki","year":"2007","journal-title":"Nat. Med."},{"key":"2021113010521941500_B33","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1152\/ajpgi.00365.2011","article-title":"Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2","volume":"302","author":"Miura","year":"2012","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"2021113010521941500_B34","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1002\/hep.24001","article-title":"Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis","volume":"52","author":"Tilg","year":"2010","journal-title":"Hepatology"},{"key":"2021113010521941500_B35","first-page":"14","article-title":"TLR9 is important for protection against intestinal damage and for intestinal repair","volume":"2","author":"Rose","year":"2012","journal-title":"Sci. Rep."}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/131\/16\/2145\/445758\/cs-2016-0838.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/131\/16\/2145\/445758\/cs-2016-0838.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T06:42:47Z","timestamp":1638254567000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/131\/16\/2145\/71639\/TLR9-is-up-regulated-in-human-and-murine-NASH"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,7,24]]},"references-count":35,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2017,8,15]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20160838","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,7,24]]}}}