Simón-Codina Blanca, Cacho-Pujol Júlia, Moles Anna, Melgar-Lesmes Pedro
Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain.
Department of Experimental Pathology, Institute of Biomedical Research of Barcelona, Spanish National Research Council (IIBB-CSIC), Barcelona, Spain.
Hepatology. 2024 Nov 12. doi: 10.1097/HEP.0000000000001160.
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 HCC. The latest single-cell and spatial transcriptomics studies have dissected unforeseen aspects depicting the immense heterogeneity of macrophages and their multifaceted role in both promoting and resolving hepatic inflammation, injury, and fibrosis. Hepatic macrophages (resident tissue KCs 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 HCC that may be of therapeutic interest for precision medicine.
前沿研究拓展了我们对肝脏疾病中巨噬细胞激活程序的理解，使这种免疫细胞类型成为一个治疗靶点。关于巨噬细胞浸润和极化状态的临床数据已被用于帮助预测肝硬化和/或肝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一些未曾预料到的方面，描绘了巨噬细胞的巨大异质性及其在促进和解决肝脏炎症、损伤及纤维化方面的多面作用。肝巨噬细胞（驻留组织 Kupffer 细胞和单核细胞衍生的巨噬细胞）表现出如此的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在肝脏的相邻区域共存。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理解肝巨噬细胞的多种调控机制和不同群体，以及设计靶向巨噬细胞的治疗干预措施以恢复肝脏内环境稳态。在此，我们综述了在肝脏疾病中调节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。我们将总结目前关于在慢性肝脏炎症、肝硬化和肝癌中激活的不同巨噬细胞程序的知识，这些知识可能对精准医学具有治疗意义。
