Dasman Diabetes Institute, Kuwait City, Kuwait.
Ministry of Health, Kuwait City, Kuwait.
Front Immunol. 2023 Jun 12;14:1195699. doi: 10.3389/fimmu.2023.1195699. eCollection 2023.
The liver is the site of first pass metabolism, detoxifying and metabolizing blood arriving from the hepatic portal vein and hepatic artery. It is made up of multiple cell types, including macrophages. These are either tissue-resident Kupffer cells (KC) of embryonic origin, or differentiated from circulating monocytes. KCs are the primary immune cells populating the liver under steady state. Liver macrophages interact with hepatocytes, hepatic stellate cells, and liver sinusoidal endothelial cells to maintain homeostasis, however they are also key contributors to disease progression. Generally tolerogenic, they physiologically phagocytose foreign particles and debris from portal circulation and participate in red blood cell clearance. However as immune cells, they retain the capacity to raise an alarm to recruit other immune cells. Their aberrant function leads to the development of non-alcoholic fatty liver disease (NAFLD). NAFLD refers to a spectrum of conditions ranging from benign steatosis of the liver to steatohepatitis and cirrhosis. In NAFLD, the multiple hit hypothesis proposes that simultaneous influences from the gut and adipose tissue (AT) generate hepatic fat deposition and that inflammation plays a key role in disease progression. KCs initiate the inflammatory response as resident immune effectors, they signal to neighbouring cells and recruit monocytes that differentiated into recruited macrophages . Recruited macrophages are central to amplifying the inflammatory response and causing progression of NAFLD to its fibro-inflammatory stages. Given their phagocytic capacity and their being instrumental in maintaining tissue homeostasis, KCs and recruited macrophages are fast-becoming target cell types for therapeutic intervention. We review the literature in the field on the roles of these cells in the development and progression of NAFLD, the characteristics of patients with NAFLD, animal models used in research, as well as the emerging questions. These include the gut-liver-brain axis, which when disrupted can contribute to decline in function, and a discussion on therapeutic strategies that act on the macrophage-inflammatory axis.
肝脏是首过代谢、解毒和代谢来自肝门静脉和肝动脉的血液的场所。它由多种细胞类型组成，包括巨噬细胞。这些细胞要么是胚胎起源的组织驻留库普弗细胞 (KC)，要么是从循环单核细胞分化而来的。KC 是在稳态下填充肝脏的主要免疫细胞。肝巨噬细胞与肝细胞、肝星状细胞和肝窦内皮细胞相互作用以维持内稳态，但它们也是疾病进展的关键贡献者。通常具有耐受性，它们生理性地吞噬门静脉循环中外来颗粒和碎片，并参与红细胞清除。然而，作为免疫细胞，它们仍然有能力发出警报以招募其他免疫细胞。它们异常的功能导致非酒精性脂肪性肝病 (NAFLD) 的发展。NAFLD 是指从良性肝脂肪变性到脂肪性肝炎和肝硬化的一系列病症。在 NAFLD 中，多击假说提出，肠道和脂肪组织 (AT) 的同时影响导致肝脏脂肪沉积，炎症在疾病进展中起着关键作用。KC 作为常驻免疫效应细胞启动炎症反应，它们向邻近细胞发出信号并招募单核细胞分化为募集的巨噬细胞。募集的巨噬细胞是放大炎症反应并导致 NAFLD 向其纤维炎症阶段进展的核心。鉴于它们的吞噬能力及其在维持组织内稳态方面的作用，KC 和募集的巨噬细胞正在迅速成为治疗干预的靶细胞类型。我们综述了该领域关于这些细胞在 NAFLD 发展和进展中的作用、NAFLD 患者的特征、研究中使用的动物模型以及新出现的问题的文献。这些问题包括肠道-肝脏-大脑轴，当该轴被破坏时，可能会导致功能下降，以及讨论作用于巨噬细胞-炎症轴的治疗策略。
