Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangzhou Higher Education Mega, Guangdong Pharmaceutical University, Lab 406, 4th Floor, Science and Technology Building, 280 Waihuan East Road, Guangzhou, China.
Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangzhou Higher Education Mega, Guangdong Pharmaceutical University, Room 403, 4th Floor, Science and Technology Building, 280 Waihuan East Road, Guangzhou, China.
Hepatol Int. 2020 Sep;14(5):652-666. doi: 10.1007/s12072-020-10081-7. Epub 2020 Sep 2.
The enrichment of innate immune cells and the enhanced inflammation represent the hallmark of non-alcoholic steatohepatitis (NASH), the advanced subtype with a significantly increased risk of progression to end-stage liver diseases within the spectrum of non-alcoholic fatty liver disease. Neutrophils are traditionally recognized as key components in the innate immune system to defend against pathogens. Recently, a growing body of evidence supports neutrophils as emerging key player in mediating the transition from steatosis to NASH, which is largely inspired by the histological findings in human liver biopsy indicating the enhanced infiltration of neutrophils as one of the key histological features of NASH. In this review, we discuss data regarding histological perspectives of hepatic infiltration of neutrophils in NASH. We also highlight the pathophysiological role of neutrophils in promoting metabolic inflammation in the liver through the release of a vast array of granule proteins, the interaction with other pro-inflammatory immune cells, and the formation of neutrophil extracellular traps. Neutrophil granule proteins possess pleiotropic effects on regulating neutrophil biology and functions. A variety of granule proteins (including lipocalin-2, myeloperoxidase, proteinase 3, neutrophil elastase, etc.) produced by neutrophils enhance liver metabolic inflammation, thereby promoting NASH progression by mediating neutrophil-macrophage interaction. Therapeutically, pharmacological inhibitors targeting neutrophil granule proteins hold promise to combat NASH. In addition, this article also summarizes potentials of neutrophils and its derived various granule proteins for the accurate, even non-invasive diagnosis of NASH.
中性粒细胞的富集和炎症的增强是非酒精性脂肪性肝炎（NASH）的标志，NASH 是一种进展为非酒精性脂肪性肝病谱中终末期肝病风险显著增加的高级亚型。中性粒细胞传统上被认为是固有免疫系统抵御病原体的关键组成部分。最近，越来越多的证据支持中性粒细胞作为介导从脂肪变性向 NASH 转变的新兴关键因素，这主要受到人类肝活检组织学发现的启发，这些发现表明中性粒细胞的浸润增强是 NASH 的一个关键组织学特征。在这篇综述中，我们讨论了关于 NASH 中性粒细胞肝内浸润的组织学观点的数据。我们还强调了中性粒细胞通过释放大量颗粒蛋白、与其他促炎免疫细胞相互作用以及形成中性粒细胞细胞外陷阱来促进肝脏代谢炎症的病理生理作用。中性粒细胞颗粒蛋白对调节中性粒细胞生物学和功能具有多效性。中性粒细胞产生的各种颗粒蛋白（包括脂联素-2、髓过氧化物酶、蛋白酶 3、中性粒细胞弹性蛋白酶等）增强肝脏代谢炎症，从而通过介导中性粒细胞-巨噬细胞相互作用促进 NASH 的进展。在治疗方面，针对中性粒细胞颗粒蛋白的药理学抑制剂具有治疗 NASH 的潜力。此外，本文还总结了中性粒细胞及其衍生的各种颗粒蛋白在 NASH 准确、甚至非侵入性诊断中的潜力。
