NEUTROPHIL EXTRACELLULAR TRAPS PROMOTE INFLAMMATION AND DEVELOPMENT OF HEPATOCELLULAR CARCINOMA IN NON-ALCOHOLIC STEATOHEPATITIS

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 NA...

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Published in:Hepatology (Baltimore, Md.) Md.), 2018-07, Vol.68 (4), p.1347-1360
Main Authors: van der Windt, Dirk J., Sud, Vikas, Zhang, Hongji, Varley, Patrick R., Goswami, Julie, Yazdani, Hamza O., Tohme, Samer, Loughran, Patricia, O’Doherty, Robert M., Minervini, Marta I., Huang, Hai, Simmons, Richard L., Tsung, Allan
Format: Article
Language:English
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Summary: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 greatly 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 was seen, and was followed by an influx of monocyte-derived macrophages, production of inflammatory cytokines, and progression of HCC. Inhibiting NET formation, through treatment with 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.
ISSN:0270-9139
1527-3350
DOI:10.1002/hep.29914