{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:08:54Z","timestamp":1790762934345,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T00:00:00Z","timestamp":1698019200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Korea Government","award":["2022R1C1C1003563"],"award-info":[{"award-number":["2022R1C1C1003563"]}]},{"name":"2022 BK21 FOUR Program of Pusan National University","award":["2022R1C1C1003563"],"award-info":[{"award-number":["2022R1C1C1003563"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nonalcoholic steatohepatitis (NASH) is an advanced stage of fatty liver disease characterized by liver damage, inflammation, and fibrosis. Although neutrophil infiltration is consistently observed in the livers of patients with NASH, the precise role of neutrophil-recruiting chemokines and infiltrating neutrophils in NASH pathogenesis remains poorly understood. Here, we aimed to elucidate the role of neutrophil infiltration in the transition from fatty liver to NASH by examining hepatic overexpression of interleukin-8 (IL8), a major chemokine responsible for neutrophil recruitment in humans. Mice fed a high-fat diet (HFD) for 3 months developed fatty liver without concurrent liver damage, inflammation, and fibrosis. Subsequent infection with an adenovirus overexpressing human IL8 for an additional 2 weeks increased IL8 levels, neutrophil infiltration, and liver injury in mice. Mechanistically, IL8-induced liver injury was associated with the upregulation of components of the NADPH oxidase 2 complex, which participate in neutrophil oxidative burst. IL8-driven neutrophil infiltration promoted macrophage aggregate formation and upregulated the expression of chemokines and inflammatory cytokines. Notably, IL8 overexpression amplified factors associated with fibrosis, including collagen deposition and hepatic stellate cell activation, in HFD-fed mice. Collectively, hepatic overexpression of human IL8 promotes neutrophil infiltration and fatty liver progression to NASH in HFD-fed mice.<\/jats:p>","DOI":"10.3390\/ijms242015489","type":"journal-article","created":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T10:32:24Z","timestamp":1698057144000},"page":"15489","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Overexpression of Interleukin-8 Promotes the Progression of Fatty Liver to Nonalcoholic Steatohepatitis in Mice"],"prefix":"10.3390","volume":"24","author":[{"given":"Ye Eun","family":"Cho","sequence":"first","affiliation":[{"name":"College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeonsoo","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung-Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 24341, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haeseung","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9728-3603","authenticated-orcid":false,"given":"Seonghwan","family":"Hwang","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"},{"name":"Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Vairetti, M., Colucci, G., and Ferrigno, A. (2022). Innovative Molecular Target and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease\/Nonalcoholic Steatohepatitis (NAFLD\/NASH) 2.0. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23147894"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"D\u00edaz, L.A., Arab, J.P., Louvet, A., Bataller, R., and Arrese, M. (2023). The intersection between alcohol-related liver disease and nonalcoholic fatty liver disease. Nat. Rev. Gastroenterol. Hepatol., online ahead of print.","DOI":"10.1038\/s41575-023-00822-y"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/nrgastro.2017.109","article-title":"Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention","volume":"15","author":"Younossi","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Younossi, Z.M., Zelber-Sagi, S., Henry, L., and Gerber, L.H. (2023). Lifestyle interventions in nonalcoholic fatty liver disease. Nat. Rev. Gastroenterol. Hepatol.","DOI":"10.1038\/s41575-023-00800-4"},{"key":"ref_5","first-page":"167","article-title":"Pathogenesis and Prevention of Hepatic Steatosis","volume":"11","author":"Nassir","year":"2015","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1053\/j.gastro.2020.01.052","article-title":"Nonalcoholic Fatty Liver Disease 2020: The State of the Disease","volume":"158","author":"Cotter","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.cell.2021.04.015","article-title":"Mechanisms and disease consequences of nonalcoholic fatty liver disease","volume":"184","author":"Loomba","year":"2021","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.jhep.2023.03.038","article-title":"An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH","volume":"79","author":"Tacke","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1056\/NEJM198902093200606","article-title":"Tissue destruction by neutrophils","volume":"320","author":"Weiss","year":"1989","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/nri1785","article-title":"Neutrophils and immunity: Challenges and opportunities","volume":"6","author":"Nathan","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Nguyen, G.T., Green, E.R., and Mecsas, J. (2017). Neutrophils to the ROScue: Mechanisms of NADPH Oxidase Activation and Bacterial Resistance. Front. Cell Infect. Microbiol., 7.","DOI":"10.3389\/fcimb.2017.00373"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1007\/s00441-017-2785-7","article-title":"Neutrophils in tissue injury and repair","volume":"371","author":"Wang","year":"2018","journal-title":"Cell Tissue Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2629","DOI":"10.1172\/JCI124616","article-title":"More friend than foe: The emerging role of neutrophils in tissue repair","volume":"129","author":"Peiseler","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/s41423-023-00974-6","article-title":"The chemokines CXCL8 and CXCL12: Molecular and functional properties, role in disease and efforts towards pharmacological intervention","volume":"20","author":"Cambier","year":"2023","journal-title":"Cell. Mol. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1111\/j.1478-3231.2011.02639.x","article-title":"Neutrophil to lymphocyte ratio: A new marker for predicting steatohepatitis and fibrosis in patients with nonalcoholic fatty liver disease","volume":"32","author":"Alkhouri","year":"2012","journal-title":"Liver Int."},{"key":"ref_16","first-page":"278","article-title":"Neutrophil-Lymphocyte Ratio (NLR) Could Be Better Predictor than C-reactive Protein (CRP) for Liver Fibrosis in Non-alcoholic Steatohepatitis(NASH)","volume":"45","author":"Yilmaz","year":"2015","journal-title":"Ann. Clin. Lab. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Bertola, A., Bonnafous, S., Anty, R., Patouraux, S., Saint-Paul, M.C., Iannelli, A., Gugenheim, J., Barr, J., Mato, J.M., and Le Marchand-Brustel, Y. (2010). Hepatic expression patterns of inflammatory and immune response genes associated with obesity and NASH in morbidly obese patients. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0013577"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nri3399","article-title":"Neutrophil recruitment and function in health and inflammation","volume":"13","author":"Kolaczkowska","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1053\/j.gastro.2016.01.025","article-title":"Inflammation in Alcoholic and Nonalcoholic Fatty Liver Disease: Friend or Foe?","volume":"150","author":"Gao","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1002\/JLB.3A0820-207R","article-title":"Neutrophil recruitment by chemokines Cxcl1\/KC and Cxcl2\/MIP2: Role of Cxcr2 activation and glycosaminoglycan interactions","volume":"109","author":"Sawant","year":"2021","journal-title":"J. Leukoc. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"20545","DOI":"10.1074\/jbc.271.34.20545","article-title":"The CXC chemokines growth-regulated oncogene (GRO) alpha, GRObeta, GROgamma, neutrophil-activating peptide-2, and epithelial cell-derived neutrophil-activating peptide-78 are potent agonists for the type B, but not the type A, human interleukin-8 receptor","volume":"271","author":"Ahuja","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.cytogfr.2016.08.002","article-title":"The CXCL8-CXCR1\/2 pathways in cancer","volume":"31","author":"Liu","year":"2016","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5183","DOI":"10.4049\/jimmunol.181.8.5183","article-title":"Homeostatic regulation of blood neutrophil counts","volume":"181","author":"Ley","year":"2008","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1136\/gutjnl-2016-311861","article-title":"MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6-p47(phox)-oxidative stress pathway in neutrophils","volume":"66","author":"Li","year":"2017","journal-title":"Gut"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1002\/hep.31390","article-title":"Protective and Detrimental Roles of p38\u03b1 Mitogen-Activated Protein Kinase in Different Stages of Nonalcoholic Fatty Liver Disease","volume":"72","author":"Hwang","year":"2020","journal-title":"Hepatology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1002\/hep.31031","article-title":"Interleukin-22 Ameliorates Neutrophil-Driven Nonalcoholic Steatohepatitis Through Multiple Targets","volume":"72","author":"Hwang","year":"2020","journal-title":"Hepatology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"eaba4448","DOI":"10.1126\/scitranslmed.aba4448","article-title":"Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis","volume":"12","author":"Govaere","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2452","DOI":"10.1002\/hep.31995","article-title":"Transcriptomics Identify Thrombospondin-2 as a Biomarker for NASH and Advanced Liver Fibrosis","volume":"74","author":"Kozumi","year":"2021","journal-title":"Hepatology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1042\/bj3220317","article-title":"Quantification of malondialdehyde and 4-hydroxynonenal adducts to lysine residues in native and oxidized human low-density lipoprotein","volume":"322","author":"Requena","year":"1997","journal-title":"Biochem. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.freeradbiomed.2016.10.497","article-title":"4-Hydroxynonenal (HNE) modified proteins in metabolic diseases","volume":"111","author":"Castro","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Itoh, M., Kato, H., Suganami, T., Konuma, K., Marumoto, Y., Terai, S., Sakugawa, H., Kanai, S., Hamaguchi, M., and Fukaishi, T. (2013). Hepatic crown-like structure: A unique histological feature in non-alcoholic steatohepatitis in mice and humans. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0082163"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5368","DOI":"10.1128\/JVI.78.10.5368-5381.2004","article-title":"Analysis of adenovirus sequestration in the liver, transduction of hepatic cells, and innate toxicity after injection of fiber-modified vectors","volume":"78","author":"Shayakhmetov","year":"2004","journal-title":"J. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"29355","DOI":"10.1016\/S0021-9258(18)43882-3","article-title":"The murine interleukin 8 type B receptor homologue and its ligands. Expression and biological characterization","volume":"269","author":"Bozic","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1002\/jlb.64.4.494","article-title":"The murine neutrophil-chemoattractant chemokines LIX, KC, and MIP-2 have distinct induction kinetics, tissue distributions, and tissue-specific sensitivities to glucocorticoid regulation in endotoxemia","volume":"64","author":"Rovai","year":"1998","journal-title":"J. Leukoc. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2573","DOI":"10.1002\/eji.200526021","article-title":"Human CXCR2 (hCXCR2) takes over functionalities of its murine homolog in hCXCR2 knockin mice","volume":"35","author":"Mihara","year":"2005","journal-title":"Eur. J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4446","DOI":"10.1038\/s41598-020-61441-0","article-title":"Therapeutic mechanism of cord blood mononuclear cells via the IL-8-mediated angiogenic pathway in neonatal hypoxic-ischaemic brain injury","volume":"10","author":"Cho","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.4049\/jimmunol.155.4.2158","article-title":"Chemokine binding and activities mediated by the mouse IL-8 receptor","volume":"155","author":"Lee","year":"1995","journal-title":"J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/nri2506","article-title":"Myeloid-derived suppressor cells as regulators of the immune system","volume":"9","author":"Gabrilovich","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/B978-0-12-405881-1.00002-1","article-title":"Reactive oxygen species in the activation of MAP kinases","volume":"528","author":"Son","year":"2013","journal-title":"Methods Enzymol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1002\/jcp.1041400226","article-title":"Production of transforming growth factor beta by human peripheral blood monocytes and neutrophils","volume":"140","author":"Grotendorst","year":"1989","journal-title":"J. Cell. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1172\/JCI88881","article-title":"Liver inflammation and fibrosis","volume":"127","author":"Koyama","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.jcmgh.2018.01.003","article-title":"Neutrophil-Hepatic Stellate Cell Interactions Promote Fibrosis in Experimental Steatohepatitis","volume":"5","author":"Zhou","year":"2018","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1038\/nm.2885","article-title":"Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase","volume":"18","author":"Talukdar","year":"2012","journal-title":"Nat. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.bbrc.2019.08.111","article-title":"Knockout of neutrophil elastase protects against western diet induced nonalcoholic steatohepatitis in mice by regulating hepatic ceramides metabolism","volume":"518","author":"Chen","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1002\/hep4.1566","article-title":"Therapeutic Targeting of Myeloperoxidase Attenuates NASH in Mice","volume":"4","author":"Koop","year":"2020","journal-title":"Hepatol. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1053\/j.gastro.2012.09.057","article-title":"Mice that express human interleukin-8 have increased mobilization of immature myeloid cells, which exacerbates inflammation and accelerates colon carcinogenesis","volume":"144","author":"Asfaha","year":"2013","journal-title":"Gastroenterology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15489\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:10:27Z","timestamp":1760130627000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15489"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,23]]},"references-count":46,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ijms242015489"],"URL":"https:\/\/doi.org\/10.3390\/ijms242015489","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,23]]}}}