Bonacina Fabrizia, Zhang Xiangyu, Manel Nicolas, Yvan-Charvet Laurent, Razani Babak, Norata Giuseppe D
Department of Excellence of Pharmacological and Biomolecular Sciences 'Rodolfo Paoletti', Università degli Studi di Milano, Milan, Italy.
Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA.
Nat Rev Cardiol. 2025 Mar;22(3):149-164. doi: 10.1038/s41569-024-01072-4. Epub 2024 Sep 20.
Lysosomes have a central role in the disposal of extracellular and intracellular cargo and also function as metabolic sensors and signalling platforms in the immunometabolic reprogramming of macrophages and other immune cells in atherosclerosis. Lysosomes can rapidly sense the presence of nutrients within immune cells, thereby switching from catabolism of extracellular material to the recycling of intracellular cargo. Such a fine-tuned degradative response supports the generation of metabolic building blocks through effectors such as mTORC1 or TFEB. By coupling nutrients to downstream signalling and metabolism, lysosomes serve as a crucial hub for cellular function in innate and adaptive immune cells. Lysosomal dysfunction is now recognized to be a hallmark of atherogenesis. Perturbations in nutrient-sensing and signalling have profound effects on the capacity of immune cells to handle cholesterol, perform phagocytosis and efferocytosis, and limit the activation of the inflammasome and other inflammatory pathways. Strategies to improve lysosomal function hold promise as novel modulators of the immunoinflammatory response associated with atherosclerosis. In this Review, we describe the crosstalk between lysosomal biology and immune cell function and polarization, with a particular focus on cellular immunometabolic reprogramming in the context of atherosclerosis.
溶酶体在细胞外和细胞内物质的处理中发挥着核心作用，并且在动脉粥样硬化中巨噬细胞和其他免疫细胞的免疫代谢重编程过程中，还充当代谢传感器和信号平台。溶酶体能够快速感知免疫细胞内营养物质的存在，从而从细胞外物质的分解代谢转变为细胞内物质的循环利用。这种精确调节的降解反应通过mTORC1或TFEB等效应物支持代谢构件的生成。通过将营养物质与下游信号传导和代谢相耦合，溶酶体成为先天免疫细胞和适应性免疫细胞中细胞功能的关键枢纽。现在人们认识到溶酶体功能障碍是动脉粥样硬化形成的一个标志。营养感知和信号传导的紊乱对免疫细胞处理胆固醇、进行吞噬作用和胞葬作用的能力以及限制炎性小体和其他炎症途径的激活具有深远影响。改善溶酶体功能的策略有望成为与动脉粥样硬化相关的免疫炎症反应的新型调节剂。在本综述中，我们描述了溶酶体生物学与免疫细胞功能和极化之间的相互作用，特别关注动脉粥样硬化背景下的细胞免疫代谢重编程。
