Cutting-edge research has expanded our understanding of the macrophage activation programs in liver diseases making this immune cell type a therapeutic target. Clinical data on macrophage infiltration and polarization states have been used to help predict mortality or poor prognosis in patients with liver cirrhosis and/or hepatocellular carcinoma. The latest single-cell and spatial transcriptomics studies have dissected unforeseen aspects depicting the immense heterogeneity of macrophages and their multifaceted role on both promoting and resolving hepatic inflammation, injury, and fibrosis. Hepatic macrophages (resident tissue Kupffer cells and monocyte-derived macrophages) display such plasticity and phenotypic diversity that macrophages with antagonistic functions may coexist in adjacent regions of the liver. In this scenario, the analysis of macrophage-derived inflammatory and anti-inflammatory circulating soluble markers in patients with liver disease only offers a partial picture of the full complexity of the hepatic macrophage subsets. The reprogramming of macrophages involves understanding the multiple regulatory mechanisms and diverse populations of hepatic macrophages and the design of macrophage-targeted therapeutic interventions to restore hepatic homeostasis. Here we review the potential targets to modulate macrophage behavior in liver diseases and nanoscale therapeutics that aim to target and treat macrophages. We will summarize current knowledge on the diverse macrophage programs activated in chronic liver inflammation, cirrhosis and hepatocellular carcinoma that may be of therapeutic interest for precision medicine.

中文翻译：

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重编程巨噬细胞以治疗肝脏疾病


前沿研究扩大了我们对肝病中巨噬细胞激活程序的理解，使这种免疫细胞类型成为治疗靶点。巨噬细胞浸润和极化状态的临床数据已用于帮助预测肝硬化和/或肝细胞癌患者的死亡率或不良预后。最新的单细胞和空间转录组学研究剖析了描绘巨噬细胞巨大异质性的不可预见的方面，以及它们在促进和解决肝脏炎症、损伤和纤维化方面的多方面作用。肝脏巨噬细胞（常驻组织 Kupffer 细胞和单核细胞衍生的巨噬细胞）表现出如此可塑性和表型多样性，以至于具有拮抗功能的巨噬细胞可能共存于肝脏的相邻区域。在这种情况下，对肝病患者巨噬细胞衍生的炎症和抗炎循环可溶性标志物的分析仅提供了肝脏巨噬细胞亚群全部复杂性的部分情况。巨噬细胞的重编程涉及了解肝脏巨噬细胞的多种调节机制和不同种群，以及设计巨噬细胞靶向治疗干预以恢复肝脏稳态。在这里，我们回顾了调节肝脏疾病中巨噬细胞行为的潜在靶点以及旨在靶向和治疗巨噬细胞的纳米级疗法。我们将总结有关在慢性肝脏炎症、肝硬化和肝细胞癌中激活的各种巨噬细胞程序的当前知识，这些程序可能对精准医学具有治疗意义。