Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
J Exp Med. 2019 Mar 4;216(3):556-570. doi: 10.1084/jem.20181776. Epub 2019 Feb 20.
Necrotic cell death during (Mtb) infection is considered host detrimental since it facilitates mycobacterial spread. Ferroptosis is a type of regulated necrosis induced by accumulation of free iron and toxic lipid peroxides. We observed that Mtb-induced macrophage necrosis is associated with reduced levels of glutathione and glutathione peroxidase-4 (Gpx4), along with increased free iron, mitochondrial superoxide, and lipid peroxidation, all of which are important hallmarks of ferroptosis. Moreover, necrotic cell death in Mtb-infected macrophage cultures was suppressed by ferrostatin-1 (Fer-1), a well-characterized ferroptosis inhibitor, as well as by iron chelation. Additional experiments in vivo revealed that pulmonary necrosis in acutely infected mice is associated with reduced Gpx4 expression as well as increased lipid peroxidation and is likewise suppressed by Fer-1 treatment. Importantly, Fer-1-treated infected animals also exhibited marked reductions in bacterial load. Together, these findings implicate ferroptosis as a major mechanism of necrosis in Mtb infection and as a target for host-directed therapy of tuberculosis.
在结核分枝杆菌（Mtb）感染期间，细胞发生坏死被认为对宿主有害，因为它促进了分枝杆菌的传播。铁死亡是一种由游离铁和有毒脂质过氧化物积累引起的受调控的细胞坏死形式。我们观察到，Mtb 诱导的巨噬细胞坏死与谷胱甘肽和谷胱甘肽过氧化物酶 4（Gpx4）水平降低有关，同时伴有游离铁、线粒体超氧自由基和脂质过氧化增加，这些都是铁死亡的重要标志。此外，铁死亡抑制剂 Fer-1 以及铁螯合剂均可抑制 Mtb 感染的巨噬细胞培养物中的细胞坏死。体内实验进一步表明，急性感染小鼠肺部的坏死与 Gpx4 表达降低以及脂质过氧化增加有关，Fer-1 处理同样可抑制这种坏死。重要的是，经 Fer-1 处理的感染动物的细菌载量也明显降低。这些发现表明，铁死亡是 Mtb 感染中坏死的主要机制，也是结核病宿主导向治疗的一个靶点。
