Reactive oxygen species-triggered trophoblast apoptosis is initiated by endoplasmic reticulum stress via activation of caspase-12, CHOP, and the JNK pathway in Toxoplasma gondii infection in mice
Authors: Li Yu
Xiucai Xu
Xingxing Huo
Qingli Luo
Qing Li
Aimei Zhang
Lili Liu
Zhaowu Chen
Tingting Liu
Zhao-rong Lun
Jilong Shen
Journal: Infection and Immunity (2012)
Discipline: IMMUNOLOGY
Keywords: Toxoplasma gondii infection; pregnant women; abortion; fetal teratogenesis; reactive oxygen species (ROS)
Affiliations: Anhui Provincial Laboratories of Pathogen Biology and Zoonoses, Department of Microbiology and Parasitology, Anhui Medical University, Hefei, China., Anhui Provincial Laboratories of Pathogen Biology and Zoonoses, Department of Microbiology and Parasitology, Anhui Medical University, Hefei, China, Central Laboratory of Affiliated Provincial Hospital of Anhui Medical University, Hefei, China, Department of Laboratory Diagnosis, the Fourth Affiliated Hospital of Anhui Medical University, Hefei, China, Center for Parasitic Organisms, State Key Laboratory of Biocontrol, School of Life Sciences and Key Laboratory of Tropical Diseases and Control of the Ministry of Education, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, China

Abstract:  Toxoplasma gondii infection in pregnant women may result in abortion or in fetal teratogenesis; however, the underlying mechanisms are still unclear. In this paper, based on a murine model, we showed that maternal infection with RH strain T. gondii tachyzoites induced elevated production of reactive oxygen species (ROS), local oxidative stress, and subsequent apoptosis of placental trophoblasts. PCR array analysis of 84 oxidative stress-related genes demonstrated that 27 genes were upregulated at least 2-fold and that 9 genes were downregulated at least 2-fold in the T. gondii infection group compared with levels in the control group. The expression of NADPH oxidase 1 (Nox1) and glutathione peroxidase 6 (Gpx6) increased significantly, about 25-fold. The levels of malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG) increased significantly with T. gondii infection, and levels of glutathione (GSH) decreased rapidly. T. gondii infection increased the early expression of endoplasmic reticulum stress (ERS) markers, followed by cleavage of caspase-12, activation of ASK1/JNK, and increased apoptosis of trophoblasts, both in vivo and in vitro. The apoptosis of trophoblasts, the activation of caspase-12 and the ASK1/JNK pathway, and the production of peroxides were dramatically inhibited by pretreatment with N-acetylcysteine (NAC). The upregulation of Nox1 was contact dependent and preceded the increase in levels of ERS markers and the activation of the proapoptosis cascade. Thus, we concluded that apoptosis in placental trophoblasts was initiated predominantly by ROS-mediated ERS via activation of caspase-12, CHOP, and the JNK pathway in acute T. gondii infection. Elevated ROS production is the central event in T. gondii-induced apoptosis of placental trophoblasts. 

Retracted: Yes

PubPeer comments:
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 The Retraction Notice reads:  After publication, this article was found to have evidence of data duplication or manipulation as follows: (i) regions of identity are found in the fluorescence-activated cell sorter (FACS) plots in Fig. 4A (GD10 control and GD16 control) and Fig. 4C (0 h control and co-culture), and (ii) multiple bands purporting to represent different samples appear to be identical: the first three lanes of the GRP78 panel in Fig. 7B and the CHOP panel in Fig. 7C, the p-p38 and p38 panels in Fig. 7C, and the beta-actin panels from Fig. 7B and 8C. Since the figures are not faithful representations of the original data and the original experimental data are unavailable, the authors retract this publication. We apologize to the editors and readers of Infection and Immunity and express our regret for any inconvenience this has caused. Here are the specific concerns as reported to the journal. * Figure 4A:  regions of identity are found in the fluorescence-activated cell sorter (FACS) plots in Fig. 4A (GD10 control and GD16 control) ![file] * Figure 4C:  regions of identity are found in the fluorescence-activated cell sorter (FACS) plots in Fig. 4C (0 h control and co-culture),  ![file] * Figure 7:  multiple bands purporting to represent different samples appear to be identical: the first three lanes of the GRP78 panel in Fig. 7B and the CHOP panel in Fig. 7C, the p-p38 and p38 panels in Fig. 7C, and the beta-actin panels from Fig. 7B and 8C. ![file] ![file] I thank the journal for investigating and retracting this paper. , 
 #2 The paper mentioned above has been retracted in 2015 ,