Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD.
T Lymphocyte Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD.
J Exp Med. 2022 Nov 7;219(11). doi: 10.1084/jem.20220504. Epub 2022 Sep 7.
Cellular necrosis during Mycobacterium tuberculosis (Mtb) infection promotes both immunopathology and bacterial dissemination. Glutathione peroxidase-4 (Gpx4) is an enzyme that plays a critical role in preventing iron-dependent lipid peroxidation-mediated cell death (ferroptosis), a process previously implicated in the necrotic pathology seen in Mtb-infected mice. Here, we document altered GPX4 expression, glutathione levels, and lipid peroxidation in patients with active tuberculosis and assess the role of this pathway in mice genetically deficient in or overexpressing Gpx4. We found that Gpx4-deficient mice infected with Mtb display substantially increased lung necrosis and bacterial burdens, while transgenic mice overexpressing the enzyme show decreased bacterial loads and necrosis. Moreover, Gpx4-deficient macrophages exhibited enhanced necrosis upon Mtb infection in vitro, an outcome suppressed by the lipid peroxidation inhibitor, ferrostatin-1. These findings provide support for the role of ferroptosis in Mtb-induced necrosis and implicate the Gpx4/GSH axis as a target for host-directed therapy of tuberculosis.
分枝杆菌（Mycobacterium tuberculosis，Mtb）感染导致的细胞坏死可促进免疫病理和细菌播散。谷胱甘肽过氧化物酶 4（glutathione peroxidase-4，Gpx4）是一种在预防铁依赖性脂质过氧化介导的细胞死亡（铁死亡）中发挥关键作用的酶，该过程先前与 Mtb 感染小鼠中观察到的坏死病理有关。在这里，我们记录了在活动性结核病患者中 GPX4 表达、谷胱甘肽水平和脂质过氧化的改变，并评估了该途径在 Gpx4 基因缺失或过表达的小鼠中的作用。我们发现，感染 Mtb 的 Gpx4 缺陷型小鼠的肺部坏死和细菌负荷显著增加，而过表达该酶的转基因小鼠的细菌负荷和坏死减少。此外，在体外 Mtb 感染时，Gpx4 缺陷型巨噬细胞表现出增强的坏死，而脂质过氧化抑制剂 ferrostatin-1 可抑制这种结果。这些发现为铁死亡在 Mtb 诱导的坏死中的作用提供了支持，并提示 Gpx4/GSH 轴是结核病宿主导向治疗的靶点。
