Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and is emerging as the leading cause of cirrhosis, liver transplantation and hepatocellular carcinoma (HCC). NAFLD is a metabolic disease that is considered the hepatic manifestation of the metabolic syndrome; however, during the evolution of NAFLD from steatosis to non-alcoholic steatohepatitis (NASH), to more advanced stages of NASH with liver fibrosis, the immune system plays an integral role. Triggers for inflammation are rooted in hepatic (lipid overload, lipotoxicity, oxidative stress) and extrahepatic (gut-liver axis, adipose tissue, skeletal muscle) systems, resulting in unique immune-mediated pathomechanisms in NAFLD. In recent years, the implementation of single-cell RNA-sequencing and high dimensional multi-omics (proteogenomics, lipidomics) and spatial transcriptomics have tremendously advanced our understanding of the complex heterogeneity of various liver immune cell subsets in health and disease. In NAFLD, several emerging inflammatory mechanisms have been uncovered, including profound macrophage heterogeneity, auto-aggressive T cells, the role of unconventional T cells and platelet-immune cell interactions, potentially yielding novel therapeutics. In this review, we will highlight the recent discoveries related to inflammation in NAFLD, discuss the role of immune cell subsets during the different stages of the disease (including disease regression) and integrate the multiple systems driving inflammation. We propose a refined concept by which the immune system contributes to all stages of NAFLD and discuss open scientific questions arising from this paradigm shift that need to be unravelled in the coming years. Finally, we discuss novel therapeutic approaches to target the multiple triggers of inflammation, including combination therapy via nuclear receptors (FXR agonists, PPAR agonists).

非酒精性脂肪性肝病 (NAFLD) 是最普遍的慢性肝病，并且正在成为肝硬化、肝移植和肝细胞癌 (HCC) 的主要原因。NAFLD 是一种代谢疾病，被认为是代谢综合征的肝脏表现；然而，在 NAFLD 从脂肪变性到非酒精性脂肪性肝炎 (NASH) 的演变过程中，再到伴有肝纤维化的 NASH 的更晚期阶段，免疫系统起着不可或缺的作用。炎症的诱因植根于肝脏（脂质超载、脂毒性、氧化应激）和肝外（肠-肝轴、脂肪组织、骨骼肌）系统，导致 NAFLD 中独特的免疫介导的病理机制。近年来，单细胞 RNA 测序和高维多组学（蛋白质组学、脂质组学）和空间转录组学极大地促进了我们对健康和疾病中各种肝脏免疫细胞亚群的复杂异质性的理解。在 NAFLD 中，已经发现了几种新兴的炎症机制，包括深刻的巨噬细胞异质性、自身攻击性 T 细胞、非常规 T 细胞的作用和血小板-免疫细胞相互作用，可能会产生新的治疗方法。在这篇综述中，我们将重点介绍与 NAFLD 炎症相关的最新发现，讨论免疫细胞亚群在疾病不同阶段（包括疾病消退）中的作用，并整合驱动炎症的多个系统。我们提出了一个完善的概念，通过该概念，免疫系统对 NAFLD 的所有阶段都有贡献，并讨论了这种范式转变产生的开放科学问题，这些问题需要在未来几年解开。最后，我们讨论了针对多种炎症触发因素的新治疗方法，包括通过核受体（FXR 激动剂、PPAR 激动剂）进行的联合治疗。