Journal of Hepatology ( IF 26.8 ) Pub Date : 2021-08-04 , DOI: 10.1016/j.jhep.2021.07.032 Han Wang 1 , Hongji Zhang 2 , Yu Wang 3 , Zachary J Brown 2 , Yujia Xia 1 , Zheng Huang 4 , Chengli Shen 2 , Zhiwei Hu 2 , Joal Beane 2 , Ephraim A Ansa-Addo 5 , Hai Huang 2 , Dean Tian 4 , Allan Tsung 2
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Background & Aims
Regulatory T-cells (Tregs) impair cancer immunosurveillance by creating an immunosuppressive environment that fosters tumor cell survival. Our previous findings demonstrated that neutrophil extracellular traps (NETs), which are involved both in innate and adaptive immunity, are abundant in livers affected by non-alcoholic steatohepatitis (NASH). However, how NETs interact with Tregs in the development of NASH-associated hepatocellular carcinoma (NASH-HCC) is not known.
Methods
A choline-deficient, high-fat diet+diethylnitrosamine mouse model and the stelic animal model were utilized for NASH-HCC and a western diet mouse model was used for NASH development. Treg depletion was achieved using FoxP3-DTR mice. RNA sequencing was used to explore the mechanism by which NETs could regulate Treg differentiation. Bioenergetic analyses of naïve CD4+ T-cells were assessed by Seahorse.
Results
Although the absolute number of CD4+ T-cells is lower in NASH livers, the Treg subpopulation is selectively increased. Depleting Tregs dramatically inhibits HCC initiation and progression in NASH. There is a positive correlation between increased NET and hepatic Treg levels. RNA sequencing data reveals that NETs impact gene expression profiles in naïve CD4+ T-cells, with the most differentially expressed genes being those involved in mitochondrial oxidative phosphorylation. By facilitating mitochondrial respiration, NETs can promote Treg differentiation. Metabolic reprogramming of naïve CD4+ T-cells by NETs requires toll-like receptor 4. Blockade of NETs in vivo using Pad4-/- mice or DNase I treatment reduces the activity of Tregs.
Conclusions
Tregs can suppress immunosurveillance in the premalignant stages of NASH. NETs facilitate the crosstalk between innate and adaptive immunity in NASH by promoting Treg activity through metabolic reprogramming. Therapies targeting NETs and Treg interactions could offer a potential strategy for preventing HCC in patients with NASH.
Lay summary
Regulatory T-cells (Tregs) can promote tumor development by suppressing cancer immunosurveillance, but their role in carcinogenesis during non-alcoholic steatohepatitis (NASH) progression is unknown. Herein, we discovered that selectively increased intrahepatic Tregs can promote an immunosuppressive environment in NASH livers. Neutrophil extracellular traps (NETs) link innate and adaptive immunity by promoting Treg differentiation via metabolic reprogramming of naïve CD4+ T-cells. This mechanism could be targeted to prevent liver cancer in patients with NASH.
中文翻译：
调节性 T 细胞和中性粒细胞胞外陷阱相互作用有助于非酒精性脂肪性肝炎的致癌作用
背景与目标
调节性 T 细胞 (Tregs) 通过创造促进肿瘤细胞存活的免疫抑制环境来削弱癌症免疫监视。我们之前的研究结果表明，参与先天性和适应性免疫的中性粒细胞胞外陷阱 (NETs) 在受非酒精性脂肪性肝炎 (NASH) 影响的肝脏中含量丰富。然而，在 NASH 相关肝细胞癌 (NASH-HCC) 的发展过程中，NETs 如何与 Tregs 相互作用尚不清楚。
方法
胆碱缺乏、高脂饮食+二乙基亚硝胺小鼠模型和stelic动物模型用于NASH-HCC，西方饮食小鼠模型用于NASH开发。使用 FoxP3-DTR 小鼠实现 Treg 耗竭。RNA测序用于探索NETs调节Treg分化的机制。Seahorse 评估了初始 CD4 + T 细胞的生物能量分析。
结果
尽管 NASH 肝脏中 CD4 + T 细胞的绝对数量较低，但 Treg 亚群选择性增加。消耗 Treg 可显着抑制 NASH 中 HCC 的发生和进展。NET 升高与肝 Treg 水平呈正相关。RNA 测序数据显示，NETs 影响幼稚 CD4 + T 细胞中的基因表达谱，其中表达差异最大的基因是那些参与线粒体氧化磷酸化的基因。通过促进线粒体呼吸，NETs 可以促进 Treg 分化。NETs对幼稚 CD4 + T 细胞的代谢重编程需要 toll 样受体 4。使用Pad4在体内阻断 NETs -/-小鼠或 DNase I 治疗会降低 Tregs 的活性。
结论
Tregs 可以抑制 NASH 癌前阶段的免疫监视。NETs 通过代谢重编程促进 Treg 活性，促进 NASH 中先天免疫和适应性免疫之间的串扰。针对 NETs 和 Treg 相互作用的疗法可以为 NASH 患者预防 HCC 提供潜在的策略。
总结
调节性 T 细胞 (Tregs) 可以通过抑制癌症免疫监视来促进肿瘤发展，但它们在非酒精性脂肪性肝炎 (NASH) 进展过程中的致癌作用尚不清楚。在这里，我们发现选择性增加的肝内 Treg 可以促进 NASH 肝脏中的免疫抑制环境。中性粒细胞胞外陷阱 (NETs) 通过幼稚 CD4 + T 细胞的代谢重编程促进 Treg 分化，将先天免疫和适应性免疫联系起来。这种机制可用于预防 NASH 患者的肝癌。
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