International immunopharmacology · 2024
The cGAS-STING pathway promotes the development of preeclampsia by upregulating autophagy: Mechanisms and implications.
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Sun Jindan, Yu Mengqi, Du Wenzhuo, Zhu Sennan, Chen Ziqi, Tao Jiayu, Zhou Yi, Chen Qiuyu, Zhao Yu, Zhang Qiong
Аннотация
OBJECTIVE: To investigate the influence and significance of cGAS-STING signaling pathway and autophagy on the occurrence and development of preeclampsia.
DESIGN: A case-control experimental study, in vitro cell culture study, and in vivo animal research.
METHODS: Human placenta tissue was collected and the differences in HE staining were observed. Immunohistochemistry and Western blot were used to verify differences in cGAS, STING and autophagy associated proteins. The PE rat model was established, the pathological changes of placenta and kidney were observed by HE staining, and the expression levels of related proteins were detected. In the lv-STING transfected HTR-8/SVneo trophoblast cell model, the expressions of autophagy indexes such as P62 and LC3 were verified by RT-PCR, Western blot and cell fluorescence experiments, and then the invasion and migration ability of cells were detected by Transwell and scrape tests. As an effective STING antagonist, C176 was administered to PE rats to observe whether it was effective in the treatment of PE disease.
RESULTS: The expression levels of cGAS, STING and autophagy related proteins were increased in human and rat placental tissues. In the HTR-8/SVneo cell model which transfected by lv-STING, the expression levels of autophagy related indicators such as P62 and LC3 were increased. The invasion and migration ability of HTR-8/SVneo cells were significantly inhibited, which was improved by the autophagy inhibitor chloroquine. Acting as an effective STING antagonist in vivo, C176 significantly reversed the outcome of PE, alleviated and prevented the occurrence and development of PE.
CONCLUSION: Our study proved that the cGAS-STING signaling pathway and autophagy levels are elevated in preeclampsia disease, and the cGAS-STING signaling pathway promotes the occurrence and development of preeclampsia through up-regulation of autophagy. This finding provides new insights into the pathogenesis of preeclampsia. Targeting this pathway may provide a potential therapeutic strategy for the treatment of preeclampsia.
DESIGN: A case-control experimental study, in vitro cell culture study, and in vivo animal research.
METHODS: Human placenta tissue was collected and the differences in HE staining were observed. Immunohistochemistry and Western blot were used to verify differences in cGAS, STING and autophagy associated proteins. The PE rat model was established, the pathological changes of placenta and kidney were observed by HE staining, and the expression levels of related proteins were detected. In the lv-STING transfected HTR-8/SVneo trophoblast cell model, the expressions of autophagy indexes such as P62 and LC3 were verified by RT-PCR, Western blot and cell fluorescence experiments, and then the invasion and migration ability of cells were detected by Transwell and scrape tests. As an effective STING antagonist, C176 was administered to PE rats to observe whether it was effective in the treatment of PE disease.
RESULTS: The expression levels of cGAS, STING and autophagy related proteins were increased in human and rat placental tissues. In the HTR-8/SVneo cell model which transfected by lv-STING, the expression levels of autophagy related indicators such as P62 and LC3 were increased. The invasion and migration ability of HTR-8/SVneo cells were significantly inhibited, which was improved by the autophagy inhibitor chloroquine. Acting as an effective STING antagonist in vivo, C176 significantly reversed the outcome of PE, alleviated and prevented the occurrence and development of PE.
CONCLUSION: Our study proved that the cGAS-STING signaling pathway and autophagy levels are elevated in preeclampsia disease, and the cGAS-STING signaling pathway promotes the occurrence and development of preeclampsia through up-regulation of autophagy. This finding provides new insights into the pathogenesis of preeclampsia. Targeting this pathway may provide a potential therapeutic strategy for the treatment of preeclampsia.