羟氯喹通过抑制由抗磷脂综合征引起的上皮外滋养细胞过度自噬来改善妊娠结局

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-05-06 DOI:10.1016/j.intimp.2025.114749

Shenglong Ye , Xin Yu , Wentong Jia , Wenlong Li , Yan-Ling Wang , Yongqing Wang

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引用次数: 0

摘要

目的探讨羟氯喹（HCQ）免疫调节治疗改善抗磷脂综合征（APS）所致复发性流产（RM）不良妊娠结局的作用机制。方法(1)采用免疫荧光染色法分析正常早孕母胎界面抗磷脂抗体的潜在靶点；（ii）应用免疫组织化学和免疫荧光技术比较分析正常和APS致复发性流产（APS- rm）妊娠早期胎盘蜕膜组织血管重构、绒毛组织合成分泌功能、滋养细胞自噬和凋亡水平；（iii）用正常和APS-RM患者血清处理HTR8/SVneo和BeWo细胞株，采用RT-PCR和Western blot定量分析细胞侵袭、分泌、自噬和凋亡相关分子的表达水平；（iv）在经血清处理的细胞系中加入0.1 μg/ml HCQ，检测细胞自噬和侵袭相关蛋白的表达，并通过transwell实验和成管实验评估HTR8/SVneo细胞的侵袭和成管情况。结果(i)β2-糖蛋白Ⅰ抗原在妊娠早期母胎界面各类型滋养细胞中均有表达；（ii） APS-RM患者蜕膜外滋养细胞（EVTs）自噬过度，子宫螺旋动脉重构不足；（iii） APS-RM病例血清可导致细胞过度自噬，减少细胞侵袭和试管形成；（iv） 0.1 μg/ml HCQ对体外HTR8/SVneo细胞有明显的修复作用；(v) APS病例血清主要影响evt的侵袭和成管，但对绒毛滋养细胞功能影响不大。结论磷脂抗体可导致evt过度自噬，从而影响螺旋动脉的侵袭和重塑能力，这是导致妊娠不良结局的机制之一。HCQ可以通过抑制过度自噬来挽救APS患者的不良妊娠结局。

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Hydroxychloroquine improves pregnancy outcomes by inhibiting excessive autophagy in extravillous trophoblast caused by an anti-phospholipid syndrome

Objectives

This study aims to investigate the mechanism of hydroxychloroquine (HCQ) immunoregulation therapy in improving adverse pregnancy outcomes of recurrent miscarriages (RM) caused by antiphospholipid syndrome (APS).

Methods

(i) Immunofluorescence staining was used to analyse the potential targets of antiphospholipid antibodies at the maternal-fetal interface in normal early pregnancy; (ii) Immunohistochemical and immunofluorescence techniques were used to compare and analyse the placenta vascular remodeling, villus tissue synthetic secretion function, trophoblastic autophagy and apoptosis levels in first trimester decidual tissue between normal and APS caused recurrent miscarriages (APS-RM) cases; (iii) HTR8/SVneo and BeWo cell lines were treated with serum from normal and APS-RM cases, and quantified by RT-PCR and Western blot to analysis the expression levels of cell invasion, secretion, autophagy and apoptosis-related molecules; (iv) After adding 0.1 μg/ml HCQ to the serum-treated cell line, the expression of autophagy and invasion-related proteins were detected, and invasion and tube formation of HTR8/SVneo cells was assessed by transwell experiments and tube formation assay.

Results

(i)β₂-glycoprotein Ⅰ antigen is expressed in all types of trophoblasts at the maternal-fetal interface in first trimester; (ii) The extravillous trophoblast cells (EVTs) have excessive autophagy in the decidual tissue of the APS-RM cases, and the uterine spiral artery was remodelled insufficiently; (iii) APS-RM cases serum can lead to cell excessive autophagy, and decrease cell invasion and tube formation in vitro; (iv) 0.1 μg/ml HCQ could rescue abnormal cell status caused by APS cases serum in HTR8/SVneo cells in vitro; (v) APS cases serum mainly affects the invasion and tube formation of EVTs, but has little effect on the function of villous trophoblast cells.

Conclusions

Antiphospholipid antibodies can lead to excessive autophagy in EVTs, thereby affecting ability of invasion and remodeling of spiral arteries, which is one of the mechanisms leading to adverse pregnancy outcomes. HCQ can rescue adverse pregnancy outcomes in APS patients by inhibiting excessive autophagy.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.