摘要
The essential trace element iron regulates a wide range of biological processes in virtually all living organisms.Because both iron deficiency and iron overload can lead to various pathological conditions,iron homeostasis is tightly regulated,and understanding this complex process will help pave the way to developing new therapeutic strategies for inflammatory disease.In recent years,significant progress has been made with respect to elucidating the roles of iron and iron-related genes in the development and maintenance of the immune system.Here,we review the timing and mechanisms by which systemic and cellular iron metabolism are regulated during the inflammatory response and during infectious disease,processes in which both the host and the pathogen compete for iron.We also discuss the evidence and implications that immune cells such as macrophages,T cells,and B cells require sufficient amounts of iron for their proliferation and for mediating their effector functions,in which iron serves as a co-factor in toll-like receptor 4(TLR4)signaling,mitochondrial respiration,posttranslational regulation,and epigenetic modification.In addition,we discuss the therapeutic implications of targeting ferroptosis,iron homeostasis and/or iron metabolism with respect to conferring protection against pathogen infection,controlling inflammation,and improving the efficacy of immunotherapy.
铁作为必需微量元素,参与调控机体重要生理过程,其稳态代谢对于维护机体健康至关重要.铁稳态代谢的维持受到严密而精细地调控,一旦稳态失调控而导致的铁过载或铁缺乏均可引发多种疾病.大量研究成果揭示铁离子及其转运体和铁代谢相关基因在维持免疫系统稳态过程中发挥重要作用,深入理解铁稳态调控网络有助于为免疫相关疾病开拓新型防治策略.本文综述了炎症反应和感染性疾病发生发展过程中细胞铁稳态变化规律及分子机制、宿主与病原体对铁摄取及竞争机制等最新研究进展;深入讨论了铁稳态代谢调控巨噬细胞、B细胞、T细胞等免疫细胞增殖、分化及其发挥效应的分子机理,包括铁作为辅助因子参与免疫细胞内TLR4信号通路的调控、线粒体氧化呼吸链的传递、转录后调控以及表观遗传修饰等;总结了靶向铁死亡或铁稳态代谢在抵抗病原体感染、调节炎症以及提升免疫治疗等方面的临床前期最新研究成果,讨论与展望了这些重要策略在临床治疗应用的广阔前景.
基金
This work was supported by the National Natural Science Foundation of China(31930057 and 31970689)
the National Key Research and Development Program(2018YFA0507802,2018YFA0507801,and 2018YFC2000405).
