{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T18:48:01Z","timestamp":1791398881149,"version":"4.3.3"},"reference-count":45,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,6,1]],"date-time":"2024-06-01T00:00:00Z","timestamp":1717200000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute on Alcohol Abuse and Alcoholism","award":["R01AA017729"],"award-info":[{"award-number":["R01AA017729"]}]},{"name":"National Institute on Alcohol Abuse and Alcoholism","award":["R01AA011576"],"award-info":[{"award-number":["R01AA011576"]}]},{"name":"National Institute on Alcohol Abuse and Alcoholism","award":["U01AA026933"],"award-info":[{"award-number":["U01AA026933"]}]},{"name":"National Institute on Alcohol Abuse and Alcoholism","award":["P30DK034854"],"award-info":[{"award-number":["P30DK034854"]}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["R01AA017729"],"award-info":[{"award-number":["R01AA017729"]}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["R01AA011576"],"award-info":[{"award-number":["R01AA011576"]}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["U01AA026933"],"award-info":[{"award-number":["U01AA026933"]}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases","award":["P30DK034854"],"award-info":[{"award-number":["P30DK034854"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Binge drinking in obese patients positively correlates with accelerated liver damage and liver-related death. However, the underlying mechanism and the effect of alcohol use on the progression of metabolic-dysfunction-associated steatotic liver disease (MASLD) remain unexplored. Here, we show that short-term feeding of a metabolic-dysfunction-associated steatohepatitis (MASH) diet plus daily acute alcohol binges for three days induce liver injury and activation of the NLRP3 inflammasome. We identify that a MASH diet plus acute alcohol binges promote liver inflammation via increased infiltration of monocyte-derived macrophages, neutrophil recruitment, and NET release in the liver. Our results suggest that both monocyte-derived macrophages and neutrophils are activated via NLRP3, while the administration of MCC950, an NLRP3 inhibitor, dampens these effects.In this study, we reveal important intercellular communication between hepatocytes and neutrophils. We discover that the MASH diet plus alcohol induces IL-1\u03b2 via NLRP3 activation and that IL-1\u03b2 acts on hepatocytes and promotes the production of CXCL1 and LCN2. In turn, the increase in these neutrophils recruits chemokines and causes further infiltration and activation of neutrophils in the liver. In vivo administration of the NLRP3 inhibitor, MCC950, improves the early phase of MetALD by preventing liver damage, steatosis, inflammation, and immune cells recruitment.<\/jats:p>","DOI":"10.3390\/cells13110960","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T12:29:47Z","timestamp":1717417787000},"page":"960","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Combined Insults of a MASH Diet and Alcohol Binges Activate Intercellular Communication and Neutrophil Recruitment via the NLRP3-IL-1\u03b2 Axis in the Liver"],"prefix":"10.3390","volume":"13","author":[{"given":"Mrigya","family":"Babuta","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prashanth Thevkar","family":"Nagesh","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditi Ashish","family":"Datta","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Remotti","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4955-7146","authenticated-orcid":false,"given":"Yuan","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeeval","family":"Mehta","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2608-5363","authenticated-orcid":false,"given":"Francesca","family":"Lami","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9626-8820","authenticated-orcid":false,"given":"Yanbo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gyongyi","family":"Szabo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.jhep.2023.03.017","article-title":"Global burden of liver disease: 2023 update","volume":"79","author":"Devarbhavi","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Rehm, J., and Shield, K.D. (2019). Global Burden of Alcohol Use Disorders and Alcohol Liver Disease. Biomedicines, 7.","DOI":"10.3390\/biomedicines7040099"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.3350\/cmh.2022.0365","article-title":"Global incidence and prevalence of nonalcoholic fatty liver disease","volume":"29","author":"Teng","year":"2023","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_4","first-page":"100525","article-title":"Burden of high-risk phenotype of heavy alcohol consumption among obese U.S. population: Results from National Health and Nutrition Examination Survey, 1999\u20132020","volume":"23","author":"Raza","year":"2023","journal-title":"Lancet Reg. Health Am."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.jhep.2017.11.006","article-title":"The bidirectional impacts of alcohol consumption and the metabolic syndrome: Cofactors for progressive fatty liver disease","volume":"68","author":"Boyle","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"100101","DOI":"10.1016\/j.jhepr.2020.100101","article-title":"Combined alcoholic and non-alcoholic steatohepatitis","volume":"2","author":"Wandji","year":"2020","journal-title":"JHEP Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1016\/j.cgh.2018.11.033","article-title":"Effects of Alcohol Consumption and Metabolic Syndrome on Mortality in Patients with Nonalcoholic and Alcohol-Related Fatty Liver Disease","volume":"17","author":"Younossi","year":"2019","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1111\/liv.15081","article-title":"Long-term prognosis of patients with alcohol-related liver disease or non-alcoholic fatty liver disease according to metabolic syndrome or alcohol use","volume":"42","author":"Decraecker","year":"2022","journal-title":"Liver Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1038\/s41575-023-00822-y","article-title":"The intersection between alcohol-related liver disease and nonalcoholic fatty liver disease","volume":"20","author":"Arab","year":"2023","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/s41430-021-00923-4","article-title":"Joint associations of adiposity and alcohol consumption with liver disease-related morbidity and mortality risk: Findings from the UK Biobank","volume":"76","author":"Huang","year":"2022","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1080\/08870446.2017.1325889","article-title":"Binge drinking: Health impact, prevalence, correlates and interventions","volume":"32","author":"Kuntsche","year":"2017","journal-title":"Psychol. Health"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"E93","DOI":"10.1097\/HEP.0000000000000696","article-title":"Reply: A multi-society Delphi consensus statement on new fatty liver disease nomenclature","volume":"79","author":"Lazarus","year":"2024","journal-title":"Hepatology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1146\/annurev-pathmechdis-032521-102529","article-title":"Role of the Inflammasome in Liver Disease","volume":"17","author":"Szabo","year":"2022","journal-title":"Annu. Rev. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1016\/j.jhep.2009.03.007","article-title":"Signalling pathways in alcohol-induced liver inflammation","volume":"50","author":"Mandrekar","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/s41392-021-00687-0","article-title":"Pattern recognition receptors in health and diseases","volume":"6","author":"Li","year":"2021","journal-title":"Signal. Transduct. Target. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"780496","DOI":"10.3389\/fphar.2022.780496","article-title":"The NLRP3 Inflammasome in Non-Alcoholic Fatty Liver Disease and Steatohepatitis: Therapeutic Targets and Treatment","volume":"13","author":"Yu","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.3389\/fimmu.2017.01728","article-title":"Relevance of the NLRP3 Inflammasome in the Pathogenesis of Chronic Liver Disease","volume":"8","author":"Wu","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kelley, N., Jeltema, D., Duan, Y., and He, Y. (2019). The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133328"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1097\/HEP.0000000000000298","article-title":"Alcohol-induced extracellular ASC specks perpetuate liver inflammation and damage in alcohol-associated hepatitis even after alcohol cessation","volume":"78","author":"Babuta","year":"2023","journal-title":"Hepatology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/cmi.2016.3","article-title":"Liver immunology and its role in inflammation and homeostasis","volume":"13","author":"Robinson","year":"2016","journal-title":"Cell. Mol. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/cmi.2015.97","article-title":"Hepatocytes: A key cell type for innate immunity","volume":"13","author":"Zhou","year":"2016","journal-title":"Cell. Mol. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.4049\/jimmunol.1201719","article-title":"Neutrophil extracellular traps: Double-edged swords of innate immunity","volume":"189","author":"Kaplan","year":"2012","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.jhep.2018.07.005","article-title":"Abnormal neutrophil traps and impaired efferocytosis contribute to liver injury and sepsis severity after binge alcohol use","volume":"69","author":"Bukong","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.jhep.2022.08.029","article-title":"Neutrophil extracellular traps contribute to liver damage and increase defective low-density neutrophils in alcohol-associated hepatitis","volume":"78","author":"Cho","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Babuta, M., Morel, C., Ribeiro, M.d.C., Calenda, C., Ortega-Ribera, M., Nagesh, P.T., Copeland, C., Zhuang, Y., Wang, Y., and Cho, Y. (2024). Neutrophil Extracellular Traps activate hepatic stellate cells and monocytes via NLRP3 sensing in alcohol-induced acceleration of MASH fibrosis. Gut, Online ahead of print. May 22:gutjnl-2023-331447.","DOI":"10.1136\/gutjnl-2023-331447"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1002\/hep.27921","article-title":"Short- or long-term high-fat diet feeding plus acute ethanol binge synergistically induce acute liver injury in mice: An important role for CXCL1","volume":"62","author":"Chang","year":"2015","journal-title":"Hepatology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"24378","DOI":"10.1074\/jbc.M112.371807","article-title":"Short term high fat diet challenge promotes alternative macrophage polarization in adipose tissue via natural killer T cells and interleukin-4","volume":"287","author":"Ji","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"E388","DOI":"10.1152\/ajpendo.00179.2013","article-title":"Adipose tissue inflammation contributes to short-term high-fat diet-induced hepatic insulin resistance","volume":"305","author":"Wiedemann","year":"2013","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2474","DOI":"10.2337\/db11-0194","article-title":"Inflammation is necessary for long-term but not short-term high-fat diet-induced insulin resistance","volume":"60","author":"Lee","year":"2011","journal-title":"Diabetes"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8525","DOI":"10.3748\/wjg.v20.i26.8525","article-title":"High fat diet feeding results in gender specific steatohepatitis and inflammasome activation","volume":"20","author":"Ganz","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1186\/s12967-015-0552-7","article-title":"Progression of non-alcoholic steatosis to steatohepatitis and fibrosis parallels cumulative accumulation of danger signals that promote inflammation and liver tumors in a high fat-cholesterol-sugar diet model in mice","volume":"13","author":"Ganz","year":"2015","journal-title":"J. Transl. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1136\/gutjnl-2016-312041","article-title":"Not All Mice Are the Same: Standardization of Animal Research Data Presentation","volume":"65","author":"Omary","year":"2016","journal-title":"Gut"},{"key":"ref_33","first-page":"e50586","article-title":"Isolation, purification and labeling of mouse bone marrow neutrophils for functional studies and adoptive transfer experiments","volume":"10","author":"Swamydas","year":"2013","journal-title":"J. Vis. Exp."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1002\/hep.30766","article-title":"Dysregulated Autophagy and Lysosome Function Are Linked to Exosome Production by Micro-RNA 155 in Alcoholic Liver Disease","volume":"70","author":"Babuta","year":"2019","journal-title":"Hepatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1186\/s12933-022-01564-y","article-title":"Improvement in insulin sensitivity and prevention of high fat diet-induced liver pathology using a CXCR2 antagonist","volume":"21","author":"Phillips","year":"2022","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1016\/j.bbrc.2020.11.009","article-title":"NLRP3 inflammasome inhibitor CY-09 reduces hepatic steatosis in experimental NAFLD mice","volume":"534","author":"Wang","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"102056","DOI":"10.1016\/j.clinre.2022.102056","article-title":"Inhibition of hepatic NLRP3 inflammasome ameliorates non-alcoholic steatohepatitis\/hepatitis B\u2014Induced hepatic injury","volume":"47","author":"Chen","year":"2023","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1002\/hep.31680","article-title":"Two Faces of Neutrophils in Liver Disease Development and Progression","volume":"74","author":"Cho","year":"2021","journal-title":"Hepatology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1146\/annurev-pathmechdis-051222-015009","article-title":"Neutrophils in Physiology and Pathology","volume":"19","author":"Vicanolo","year":"2024","journal-title":"Annu. Rev. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1189\/jlb.3AB1214-590R","article-title":"Metabolic danger signals, uric acid and ATP, mediate inflammatory cross-talk between hepatocytes and immune cells in alcoholic liver disease","volume":"98","author":"Petrasek","year":"2015","journal-title":"J. Leukoc. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1002\/hep.31056","article-title":"Increased Liver Localization of Lipopolysaccharides in Human and Experimental NAFLD","volume":"72","author":"Carpino","year":"2020","journal-title":"Hepatology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.jhepr.2019.09.001","article-title":"Serum lipopolysaccharides predict advanced liver disease in the general population","volume":"1","author":"Pussinen","year":"2019","journal-title":"JHEP Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.jhep.2020.07.041","article-title":"Hepatocyte pyroptosis and release of inflammasome particles induce stellate cell activation and liver fibrosis","volume":"74","author":"Gaul","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4342","DOI":"10.4049\/jimmunol.1302039","article-title":"NLRP3 regulates neutrophil functions and contributes to hepatic ischemia-reperfusion injury independently of inflammasomes","volume":"192","author":"Inoue","year":"2014","journal-title":"J. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"E131","DOI":"10.1152\/ajpendo.00347.2013","article-title":"NF-kappaB and STAT1 control CXCL1 and CXCL2 gene transcription","volume":"306","author":"Burke","year":"2014","journal-title":"Am. J. Physiol. Endocrinol. Metab."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/11\/960\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:52:24Z","timestamp":1760107944000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/11\/960"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,1]]},"references-count":45,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["cells13110960"],"URL":"https:\/\/doi.org\/10.3390\/cells13110960","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,1]]}}}