Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis
Top Cited Papers
Open Access
- 6 April 2018
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 68 (4), 1347-1360
- https://doi.org/10.1002/hep.29914
Abstract
Nonalcoholic steatohepatitis (NASH) is a progressive, inflammatory form of fatty liver disease. It is the most rapidly rising risk factor for the development of hepatocellular carcinoma (HCC), which can arise in NASH with or without cirrhosis. The inflammatory signals promoting the progression of NASH to HCC remain largely unknown. The propensity of neutrophils to expel decondensed chromatin embedded with inflammatory proteins, known as neutrophil extracellular traps (NETs), has been shown to be important in chronic inflammatory conditions and in cancer progression. In this study, we asked whether NET formation occurs in NASH and contributes to the progression of HCC. We found elevated levels of a NET marker in serum of patients with NASH. In livers from STAM mice (NASH induced by neonatal streptozotocin and high‐fat diet), early neutrophil infiltration and NET formation were seen, followed by an influx of monocyte‐derived macrophages, production of inflammatory cytokines, and progression of HCC. Inhibiting NET formation, through treatment with deoxyribonuclease (DNase) or using mice knocked out for peptidyl arginine deaminase type IV (PAD4−/−), did not affect the development of a fatty liver but altered the consequent pattern of liver inflammation, which ultimately resulted in decreased tumor growth. Mechanistically, we found that commonly elevated free fatty acids stimulate NET formation in vitro. Conclusion: Our findings implicate NETs in the protumorigenic inflammatory environment in NASH, suggesting that their elimination may reduce the progression of liver cancer in NASH. (Hepatology 2018).Keywords
Funding Information
- National Institutes of Health (T32 AI 74490, R01‐GM95566, 1S10OD019973‐01, 1S10OD011925‐01)
- National Natural Science Foundation of China (81470902)
This publication has 40 references indexed in Scilit:
- Neutrophil extracellular traps: protagonists of cancer progression?Oncogene, 2016
- NAFLD and liver transplantation: Current burden and expected challengesJournal of Hepatology, 2016
- Inflammation in Alcoholic and Nonalcoholic Fatty Liver Disease: Friend or Foe?Gastroenterology, 2016
- Different Serum Free Fatty Acid Profiles in NAFLD Subjects and Healthy Controls after Oral Fat LoadInternational Journal of Molecular Sciences, 2016
- NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesisNature, 2016
- Genetic Landscape and Biomarkers of Hepatocellular CarcinomaGastroenterology, 2015
- Hepatocellular Carcinoma in the Absence of Cirrhosis in United States Veterans Is Associated With Nonalcoholic Fatty Liver DiseaseClinical Gastroenterology and Hepatology, 2015
- Damage‐associated molecular pattern–activated neutrophil extracellular trap exacerbates sterile inflammatory liver injuryHepatology, 2015
- A proposed role for neutrophil extracellular traps in cancer immunoeditingFrontiers in Immunology, 2013
- Hepatic free fatty acids accumulate in experimental steatohepatitis: Role of adaptive pathwaysJournal of Hepatology, 2008