Gut-derived lipopolysaccharide promotes alcoholic hepatosteatosis and subsequent hepatocellular carcinoma by stimulating neutrophil extracellular traps through toll-like receptor 4
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Background/Aims: Binge drinking leads to many disorders, including alcoholic hepatosteatosis, which is characterized by intrahepatic neutrophil infiltration and increases the risk of hepatocellular carcinoma (HCC). Molecular mechanisms may involve the migration of bacterial metabolites from the gut to the liver and the activation of neutrophil extracellular traps (NETs). Methods: Serum samples from both binge drinking and alcohol-avoiding patients were analyzed. Mouse models of chronic plus binge alcohol-induced hepatosteatosis and HCC models were used. Results: A marker of NETs formation, lipopolysaccharide (LPS), was significantly higher in alcoholic hepatosteatosis and HCC patients and mice than in controls. Intrahepatic inflammation markers and HCC-related cytokines were decreased in mice with reduced NET formation due to neutrophil elastase (NE) deletion, and liver-related symptoms of alcohol were also alleviated in NE knockout mice. Removal of intestinal bacteria with antibiotics led to decreases in markers of NETs formation and inflammatory cytokines upon chronic alcohol consumption, and development of alcoholic hepatosteatosis and HCC was also attenuated. These functions were restored upon supplementation with the bacterial product LPS. When mice lacking toll-like receptor 4 (TLR4) received chronic alcohol feeding, intrahepatic markers of NETs formation decreased, and hepatosteatosis and HCC were alleviated. Conclusions: Formation of NETs following LPS stimulation of TLR4 upon chronic alcohol use leads to increased alcoholic steatosis and subsequent HCC.
Abstract
Background/Aims: Binge drinking leads to many disorders, including alcoholic hepatosteatosis, which is characterized by intrahepatic neutrophil infiltration and increases the risk of hepatocellular carcinoma (HCC). Molecular mechanisms may involve the migration of bacterial metabolites from the gut to the liver and the activation of neutrophil extracellular traps (NETs). Methods: Serum samples from both binge drinking and alcohol-avoiding patients were analyzed. Mouse models of chronic plus binge alcohol-induced hepatosteatosis and HCC models were used. Results: A marker of NETs formation, lipopolysaccharide (LPS), was significantly higher in alcoholic hepatosteatosis and HCC patients and mice than in controls. Intrahepatic inflammation markers and HCC-related cytokines were decreased in mice with reduced NET formation due to neutrophil elastase (NE) deletion, and liver-related symptoms of alcohol were also alleviated in NE knockout mice. Removal of intestinal bacteria with antibiotics led to decreases in markers of NETs formation and inflammatory cytokines upon chronic alcohol consumption, and development of alcoholic hepatosteatosis and HCC was also attenuated. These functions were restored upon supplementation with the bacterial product LPS. When mice lacking toll-like receptor 4 (TLR4) received chronic alcohol feeding, intrahepatic markers of NETs formation decreased, and hepatosteatosis and HCC were alleviated. Conclusions: Formation of NETs following LPS stimulation of TLR4 upon chronic alcohol use leads to increased alcoholic steatosis and subsequent HCC.
참고문헌 (49)
- "lobal status report on alcohol and health 2018"[URL]
- Pekow JR, "Hepatic steatosis is associated with increased frequency of hepatocellular carcinoma in patients with hepatitis C-related cirrhosis", Cancer, 109, pp.2490~2496 (2007)
- Seitz HK, "Alcoholic liver disease", Nat Rev Dis Primers, 4, pp.16~ (2018)
- Fan JH, "Attributable causes of liver cancer mortality and incidence in china", Asian Pac J Cancer Prev, 14, pp.7251~7256 (2013)
- Hassan MM, "Risk factors for hepatocellular carcinoma : synergism of alcohol with viral hepatitis and diabetes mellitus", Hepatology, 36, pp.1206~1213 (2002)
- McGlynn KA, "The global epidemiology of hepatocellular carcinoma : present and future", Clin Liver Dis, 15, pp.223~243 (2011)
- Wieser V, "Lipocalin 2 drives neutrophilic inflammation in alcoholic liver disease", J Hepatol, 64, pp.872~880 (2016)
- Bukong TN, "Abnormal neutrophil traps and impaired efferocytosis contribute to liver injury and sepsis severity after binge alcohol use", J Hepatol, 69, pp.1145~1154 (2018)
- Arroyo R, "SP-D attenuates LPS-induced formation of human neutrophil extracellular traps(NETs), protecting pulmonary surfactant inactivation by NETs", Commun Biol, 2, pp.470~ (2019)
- Munir S, "TLR4-dependent shaping of the wound site by MSCs accelerates wound healing", EMBO Rep, 21, pp.e48777~ (2020)
- Santocki M, "On neutrophil extracellular trap(NET)removal : what we know thus far and why so little", Cells, 9, pp.2079~ (2020)
- Cichon I, "Reduced neutrophil extracellular trap(NET)formation during systemic inflammation in mice with menkes disease and wilson disease : copper requirement for NET release", Front Immunol, 10, pp.3021~ (2020)
- Huang H, "Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury", Hepatology, 62, pp.600~614 (2015)
- Wilson CL, "NFκB1is a suppressor of neutrophil-driven hepatocellular carcinoma", Nat Commun, 6, pp.6818~ (2015)
- Zhou Z, "Neutrophil-hepatic stellate cell interactions promote fibrosis in experimental steatohepatitis", Cell Mol Gastroenterol Hepatol, 5, pp.399~413 (2018)
- Kolaczkowska E, "Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature", Nat Commun, 6, pp.6673~ (2015)
- Bajaj JS, "Alcohol, liver disease and the gut microbiota", Nat Rev Gastroenterol Hepatol, 16, pp.235~246 (2019)
- Leitão HS, "Hepatic fibrosis, inflammation, and steatosis : influence on the MR viscoelastic and diffusion parameters in patients with chronic liver disease", Radiology, 283, pp.98~107 (2017)
- Gonda TA, "Chronic inflammation, the tumor microenvironment and carcinogenesis", Cell Cycle, 8, pp.2005~2013 (2009)
- Li YM, "Guidelines of prevention and treatment for alcoholic liver disease(2018, China)", J Dig Dis, 20, pp.174~180 (2019)
- Machida K, "Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog", Proc Natl Acad Sci U S A, 106, pp.1548~1553 (2009)
- Celli R, "Pathology of alcoholic liver disease", J Clin Transl Hepatol, 2, pp.103~109 (2014)
- Bertola A, "Chronic plus binge ethanol feeding synergistically induces neutrophil infiltration and liver injury in mice : a critical role for E-selectin", Hepatology, 58, pp.1814~1823 (2013)
- Li Y, "Association between alcohol consumption and cancers in the Chinese population--a systematic review and meta-analysis", PLoS One, 6, pp.e18776~ (2011)
- Brandon-Warner E, "Chronic ethanol feeding accelerates hepatocellular carcinoma progression in a sex-dependent manner in a mouse model of hepatocarcinogenesis", Alcohol Clin Exp Res, 36, pp.641~653 (2012)
- Margetts J, "Neutrophils : driving progression and poor prognosis in hepatocellular carcinoma?", Br J Cancer, 118, pp.248~257 (2018)
- Lowe PP, "Alcohol-related changes in the intestinal microbiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice", PLoS One, 12, pp.e0174544~ (2017)
- Szabo G, "Gut-liver axis in alcoholic liver disease", Gastroenterology, 148, pp.30~36 (2015)
- van der Windt DJ, "Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis", Hepatology, 68, pp.1347~1360 (2018)
- Yang LY, "Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response", J Hematol Oncol, 13, pp.3~ (2020)
- Papayannopoulos V, "Neutrophil extracellular traps in immunity and disease", Nat Rev Immunol, 18, pp.134~147 (2018)
- Du J, "Neutrophil extracellular traps induced by pro-inflammatory cytokines enhance procoagulant activity in NASH patients", Clin Res Hepatol Gastroenterol, 46, pp.101697~ (2022)
- Meroni M, "Alcohol or gut microbiota : who is the guilty?", Int J Mol Sci, 20, pp.4568~ (2019)
- Llorente C, "Gastric acid suppression promotes alcoholic liver disease by inducing overgrowth of intestinal Enterococcus", Nat Commun, 8, pp.837~ (2017)
- Bode C, "Effect of alcohol consumption on the gut", Best Pract Res Clin Gastroenterol, 17, pp.575~592 (2003)
- Bala S, "Alcohol-induced miR-155 and HDAC11 inhibit negative regulators of the TLR4 pathway and lead to increased LPS responsiveness of Kupffer cells in alcoholic liver disease", J Leukoc Biol, 102, pp.487~498 (2017)
- Ohtani N, "Role of the gut-liver axis in liver inflammation, fibrosis, and cancer : a special focus on the gut microbiota relationship", Hepatol Commun, 3, pp.456~470 (2019)
- Yan J, "The role of the liver in sepsis", Int Rev Immunol, 33, pp.498~510 (2014)
- Wartha F, "Capsule and D-alanylated lipoteichoic acids protect streptococcus pneumoniae against neutrophil extracellular traps", Cell Microbiol, 9, pp.1162~1171 (2007)
- McDonald B, "Kupffer cells and activation of endothelial TLR4 coordinate neutrophil adhesion within liver sinusoids during endotoxemia", Am J Physiol Gastrointest Liver Physiol, 305, pp.G797~G806 (2013)
- Carpino G, "Increased liver localization of lipopolysaccharides in human and experimental NAFLD", Hepatology, 72, pp.470~485 (2020)
- Toffanin S, "HCC is promoted by bacterial translocation and TLR-4 signaling : a new paradigm for chemoprevention and management", Hepatology, 56, pp.1998~2000 (2012)
- Matsumoto K, "Platelet CXCL4 mediates neutrophil extracellular traps formation in ANCA-associated vasculitis", Sci Rep, 11, pp.222~ (2021)
- Guo J, "Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis", Fibrogenesis Tissue Repair, 3, pp.21~ (2010)
- Singh V, "Vancomycin prevents fermentable fiber-induced liver cancer in mice with dysbiotic gut microbiota", Gut Microbes, 11, pp.1077~1091 (2020)
- Dapito DH, "Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4", Cancer Cell, 21, pp.504~516 (2012)
- Sung H, "Microbiota-based treatments in alcoholic liver disease", World J Gastroenterol, 22, pp.6673~6682 (2016)
- Liu Y, "A role for intestinal alkaline phosphatase in preventing liver fibrosis", Theranostics, 11, pp.14~26 (2021)
- Zhou Z, "Targeting the gut barrier for the treatment of alcoholic liver disease", Liver Res, 1, pp.197~207 (2017)
