Neutrophil extracellular traps contribute to liver damage and increase defective low-density neutrophils in alcohol-associated hepatitis,Journal of Hepatology

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Neutrophil extracellular traps contribute to liver damage and increase defective low-density neutrophils in alcohol-associated hepatitis
Journal of Hepatology ( IF 26.8 ) Pub Date : 2022-09-05 , DOI: 10.1016/j.jhep.2022.08.029
Yeonhee Cho ₁ , Terence Ndonyi Bukong ₂ , David Tornai ₃ , Mrigya Babuta ₄ , Ioannis S Vlachos ₅ , Eleni Kanata ₅ , Donna Catalano ₆ , Gyongyi Szabo ₇

Affiliation

Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA; Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA.
Armand-Frappier Sante Biotechnologie Research Center, Institut National de la Recherche Scientifique, Laval, Quebec, Canada.
Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA; Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA.
Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA; Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Background & Aims

In alcohol-associated hepatitis (AH), inflammation and neutrophil counts correlate with poor clinical outcomes. Here, we investigated how neutrophils contribute to liver damage in AH.

Methods

We isolated blood neutrophils from individuals with AH to examine neutrophil extracellular traps (NETs) and performed RNA sequencing to explore their unique characteristics.

Results

We observed a significant increase in NET production in AH. We also observed a unique low-density neutrophil (LDN) population in individuals with AH and alcohol-fed mice that was not present in healthy controls. Transcriptome analysis of peripheral LDNs and high-density neutrophils (HDNs) from individuals with AH revealed that LDNs exhibit a functionally exhausted phenotype, while HDNs are activated. Indeed, AH HDNs exhibited increased resting reactive oxygen species (ROS) production and produced more ROS upon lipopolysaccharide stimulation than control HDNs, whereas AH LDNs failed to respond to lipopolysaccharide. We show that LDNs are generated from HDNs after alcohol-induced NET release in vitro, and this LDN subset has decreased functionality, including reduced phagocytic capacity. Moreover, LDNs showed reduced homing capacity and clearance by macrophage efferocytosis; therefore, dysfunctional neutrophils could remain in the circulation and liver. Depletion of both HDNs and LDNs in vivo prevented alcohol-induced NET production and liver damage in mice. Granulocyte-colony stimulating factor treatment also ameliorated alcohol-induced liver injury in mice.

Conclusion

Neutrophils contribute to liver damage through increased NET formation which increases defective LDNs in AH. Alcohol induces phenotypic changes in neutrophils; HDNs are activated whereas LDNs are defective. Our findings provide mechanistic insights that could guide the development of therapeutic interventions for AH.

Impact and implications

In this study we discovered heterogeneity of neutrophils in alcohol-associated hepatitis, including high-density and low-density neutrophils that show hyper-activated or exhausted transcriptomic profiles, respectively. We found that alcohol induces neutrophil extracellular trap (NET) formation, which contributes to liver damage. NET release by high-density neutrophils resulted in low-density neutrophils that reside in the liver and escape clean-up by macrophages. Our findings help to understand the opposing neutrophil phenotypes observed in individuals with alcohol-associated hepatitis and provide mechanistic insights that could guide therapeutic strategies targeting neutrophils.

中文翻译：

中性粒细胞胞外陷阱会导致肝脏损伤，并增加酒精相关性肝炎中缺陷型低密度中性粒细胞的数量

背景与目标

在酒精相关性肝炎（AH）中，炎症和中性粒细胞计数与不良的临床结果相关。在这里，我们研究了中性粒细胞如何导致 AH 中的肝损伤。

方法

我们从 AH 患者中分离出血液中性粒细胞，以检查中性粒细胞胞外陷阱 (NET)，并进行 RNA 测序以探索其独特特征。

结果

我们观察到 AH 的净产量显着增加。我们还在 AH 个体和酒精喂养的小鼠中观察到了独特的低密度中性粒细胞 (LDN) 群体，而健康对照组中不存在这种情况。对 AH 患者外周 LDN 和高密度中性粒细胞 (HDN) 的转录组分析表明，LDN 表现出功能耗尽的表型，而 HDN 则被激活。事实上，AH HDN 表现出增加的静息活性氧 (ROS) 产生，并且在脂多糖刺激后产生比对照 HDN 更多的 ROS，而 AH LDN 未能对脂多糖做出反应。我们发现，LDN 是在体外酒精诱导的 NET 释放后由 HDN 产生的，并且该 LDN 子集的功能下降，包括吞噬能力下降。此外，LDN 的归巢能力和巨噬细胞胞吞作用的清除能力降低；因此，功能失调的中性粒细胞可能残留在循环系统和肝脏中。体内HDN 和 LDN 的消耗可防止酒精诱导的 NET 产生和小鼠肝脏损伤。粒细胞集落刺激因子治疗还可以减轻酒精引起的小鼠肝损伤。

结论

中性粒细胞通过增加 NET 形成而导致肝损伤，从而增加 AH 中缺陷的 LDN。酒精会引起中性粒细胞的表型变化；HDN 已激活，而 LDN 则有缺陷。我们的研究结果提供了机制见解，可以指导 AH 治疗干预措施的开发。

影响和影响

在这项研究中，我们发现酒精相关性肝炎中中性粒细胞的异质性，包括分别表现出过度激活或耗尽转录组特征的高密度和低密度中性粒细胞。我们发现酒精会诱导中性粒细胞胞外陷阱（NET）形成，从而导致肝脏损伤。高密度中性粒细胞释放的 NET 导致低密度中性粒细胞驻留在肝脏中并逃避巨噬细胞的清理。我们的研究结果有助于了解在酒精相关性肝炎患者中观察到的相反的中性粒细胞表型，并提供可以指导针对中性粒细胞的治疗策略的机制见解。

更新日期：2022-09-05

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