Placenta · 2025
Anti-β2GPI antibodies induce trophoblast pyroptosis and placental inflammation through TLR4/NLRP3/GSDMD axis.
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Xu Mingyang, Ji Xiaoyu, Zhang Hongyuan, Zeng Dongmei, Zhao Zhendong, Liu Jiayue, Zhang Lan, Dong Tingting, Chen Pengzheng, Wang Xietong
Аннотация
OBJECTIVE: Obstetric antiphospholipid syndrome (OAPS) is an autoimmune disease characterized by the persistent presence of anti-β2-glycoprotein I (anti-β2GPI) antibodies. Placental inflammation, particularly involving trophoblasts, is currently considered a key driver of OAPS pathogenesis. This article aims to explore the effect of anti-β2GPI antibodies on trophoblast pyroptosis and the underlying molecular mechanisms.
METHODS: Firstly, we collect clinical samples to test pyroptosis-related expression. Then, we assess the effects of anti-β2GPI antibodies on the biological function of trophoblast by CCK8, EDU, transwell assays and so on. Meanwhile, we detected pyroptosis-related factors by WB and qPT-PCR. In vivo experiments, we establish OAPS mouse model to study trophoblast pyroapoptosis.
RESULTS: We demonstrated that the placentas from OAPS patients exhibited distinctive histopathological alterations and elevated expression of pyroptosis-related markers. In vitro assays, we found that anti-β2GPI antibodies could impair trophoblast biological functions and upregulate trophoblast pyroptosis, an effect that could be reversed by the NLRP3 inhibitor MCC950. Furthermore, anti-β2GPI antibodies could activate the TLR4/NLRP3/GSDMD pathway, leading to trophoblast pyroptosis. Meanwhile, the TLR4 inhibitor Robinin downregulated the expression of pyroptosis-related factors and restored trophoblast biological function. Moreover, OAPS mouse models were successfully established to confirm the excessive activation of the TLR4/NLRP3/GSDMD pathway-mediated pyroptosis in vivo.
CONCLUSION: Anti-β2GPI antibodies could exacerbate trophoblast pyroptosis via the TLR4/NLRP3/GSDMD axis.
METHODS: Firstly, we collect clinical samples to test pyroptosis-related expression. Then, we assess the effects of anti-β2GPI antibodies on the biological function of trophoblast by CCK8, EDU, transwell assays and so on. Meanwhile, we detected pyroptosis-related factors by WB and qPT-PCR. In vivo experiments, we establish OAPS mouse model to study trophoblast pyroapoptosis.
RESULTS: We demonstrated that the placentas from OAPS patients exhibited distinctive histopathological alterations and elevated expression of pyroptosis-related markers. In vitro assays, we found that anti-β2GPI antibodies could impair trophoblast biological functions and upregulate trophoblast pyroptosis, an effect that could be reversed by the NLRP3 inhibitor MCC950. Furthermore, anti-β2GPI antibodies could activate the TLR4/NLRP3/GSDMD pathway, leading to trophoblast pyroptosis. Meanwhile, the TLR4 inhibitor Robinin downregulated the expression of pyroptosis-related factors and restored trophoblast biological function. Moreover, OAPS mouse models were successfully established to confirm the excessive activation of the TLR4/NLRP3/GSDMD pathway-mediated pyroptosis in vivo.
CONCLUSION: Anti-β2GPI antibodies could exacerbate trophoblast pyroptosis via the TLR4/NLRP3/GSDMD axis.