Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis.
Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis.
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中性粒细胞胞外陷阱促进非酒精性脂肪性肝炎中的炎症和肝细胞癌的发展
DOI：
10.1002/hep.29914
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Tsung A
中科院分区：
文献类型：
--
作者：
van der Windt DJ;Sud V;Zhang H;Varley PR;Goswami J;Yazdani HO;Tohme S;Loughran P;O'Doherty RM;Minervini MI;Huang H;Simmons RL;Tsung A
非酒精性脂肪性肝炎（NASH）是一种进行性的炎症性脂肪肝。它是肝细胞癌（HCC）发展的最快速上升的风险因素，肝细胞癌可在伴或不伴肝硬化的NASH中出现。促进NASH进展为HCC的炎症信号在很大程度上仍然未知。嗜中性粒细胞排出嵌入炎性蛋白质的去致密染色质的倾向，称为嗜中性粒细胞细胞外陷阱（NET），已被证明在慢性炎症性疾病和癌症进展中很重要。在这项研究中，我们询问NET形成是否发生在NASH中并有助于HCC的进展。我们发现NASH患者血清中NET标志物水平升高。在STAM小鼠的肝脏（新生儿链脲佐菌素和高脂饮食诱导的NASH）中，观察到早期中性粒细胞浸润和NET形成，随后是单核细胞衍生的巨噬细胞流入，产生炎性细胞因子和HCC进展。通过脱氧核糖核酸酶（DNase）治疗或使用肽基精氨酸脱氨酶IV型（PAD 4 −/−）敲除的小鼠抑制NET形成，不会影响脂肪肝的发展，但会改变肝脏炎症的后续模式，最终导致肿瘤生长减少。从机制上讲，我们发现，通常升高的游离脂肪酸刺激NET在体外形成。结论：我们的研究结果表明NETs在NASH的促肿瘤性炎症环境中，这表明它们的消除可能会减少NASH中肝癌的进展。（Hepatology 2018）。
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).
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影响因子：
25.7
作者：
Pais R;Barritt AS 4th;Calmus Y;Scatton O;Runge T;Lebray P;Poynard T;Ratziu V;Conti F
通讯作者：
Conti F
影响因子：
3.7
作者：
Hemmers S;Teijaro JR;Arandjelovic S;Mowen KA
通讯作者：
Mowen KA
影响因子：
5.6
作者：
Gambino R;Bugianesi E;Rosso C;Mezzabotta L;Pinach S;Alemanno N;Saba F;Cassader M
通讯作者：
Cassader M
影响因子：
7.3
作者：
Berger-Achituv S;Brinkmann V;Abed UA;Kühn LI;Ben-Ezra J;Elhasid R;Zychlinsky A
通讯作者：
Zychlinsky A
影响因子：
29.4
作者：
Gao B;Tsukamoto H
通讯作者：
Tsukamoto H