流产芽孢杆菌是在巨噬细胞内复制的兼性细胞内细菌。细胞内存活是评估布鲁氏菌毒力的重要指标之一。铁凋亡是一种由游离铁积累诱导的程序性细胞死亡,活性氧(ROS),和有毒的脂质过氧化物,在癌症中扮演角色,心血管疾病,和炎症性疾病。在这项研究中,我们发现布鲁氏菌粗糙菌株RB51在宿主谷胱甘肽和谷胱甘肽过氧化物酶4(Gpx4)水平降低的巨噬细胞上诱导铁凋亡,加上增加的亚铁,脂质过氧化,ROS。抑制因子-1显著降低RB51感染的巨噬细胞的铁凋亡,证实在布鲁氏菌RB51感染期间发生铁凋亡。此外,我们发现RB51感染诱导的铁凋亡受P53-Slc7a11-Gpx4/GSH信号通路的调控。抑制P53降低了ROS和脂质过氧化的水平,而Slc7a11,Gpx4和GSH的水平被救出。更重要的是,通过不同的铁凋亡抑制剂抑制铁凋亡增加了布鲁氏菌RB51的细胞内存活,表明铁凋亡对布鲁氏菌细胞内存活的减弱作用。总的来说,我们的观察表明,布鲁氏菌RB51感染诱导巨噬细胞的铁凋亡,它受P53-Slc7a11-Gpx4/GSH信号通路的调控,在抑制布鲁氏菌细胞内存活中起作用。
B. abortus is a facultative intracellular bacterium that replicates within macrophages. Intracellular survival is one of the important indexes to evaluate the virulence of
Brucella. Ferroptosis is a type of programmed cell death induced by the accumulation of free iron, reactive oxygen species (ROS), and toxic lipid peroxides, play roles on cancers, cardiovascular diseases, and inflammatory diseases. In this study, we found that
Brucella rough strain RB51 induced ferroptosis on macrophages with reduced levels of host glutathione and glutathione peroxidase 4 (Gpx4), together with increased ferrous iron, lipid peroxidation, and ROS. The inhibitor ferrostatin-1 significantly reduced the ferroptosis of RB51-infected macrophages, confirming that ferroptosis occurred during infection with
Brucella RB51. Furthermore, we found that RB51 infection induced ferroptosis is regulated by P53-Slc7a11-Gpx4/GSH signal pathway. Inhibiting P53 decreased the levels of ROS and lipid peroxidation, while the levels of Slc7a11, Gpx4 and GSH were rescued. More importantly, inhibiting ferroptosis by different ferroptosis inhibitors increased the intracellular survival of Brucella RB51, indicating ferroptosis functions on the attenuation of
Brucella intracellular survival. Collectively, our observations demonstrate that
Brucella RB51 infection induces ferroptosis on macrophages, which is regulated by P53-Slc7a11-Gpx4/GSH signal pathway and functions on the attenuation of intracellular survival of Brucella.