HMGB1通过介导巨噬细胞自噬诱导原因不明的复发性自然流产。

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-02-06 DOI:10.1016/j.intimp.2024.113999

Xingxing Han , Yu Ren , Xueke Zhang , Damin Zhu , Zihan Meng , Qiqi Zhang , Beili Chen , Ping Zhou , Zhaolian Wei , Yunxia Cao , Xiaofeng Xu , Zhiguo Zhang , Huijuan Zou

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引用次数: 0

摘要

背景：HMGB1在母胎界面（MFI）过表达被认为是不明原因复发性自然流产（URSA）的重要因素。本研究旨在研究URSA患者个体组织的自噬情况，探讨HMGB1与URSA MFI巨噬细胞自噬的关系。方法：收集40例URSA患者和60例主动终止妊娠妇女的人蜕膜组织。建立小鼠失孕URSA模型和体外细胞模型，分别用HMGB1抑制剂（阿司匹林）和抗HMGB1抗体处理。使用western blot分析、免疫荧光分析和透射电镜（TEM）评估MFI的自噬情况。结果：本研究发现URSA组个体组织LC3B高表达，P62低表达。这些发现通过透射电镜进一步证实。自噬在巨噬细胞内的定位表明URSA组的个体巨噬细胞的自噬明显增强。然而，低剂量阿司匹林治疗导致蛋白表达逆转和自噬减少。在体外实验中，发现重组HMGB1介导永生化骨髓源性巨噬细胞的自噬，可被抗HMGB1抗体抑制。结论：本研究首次提示MFI处HMGB1水平升高可触发巨噬细胞自噬，从而促进无菌性炎症，参与URSA的发生和进展。此外，低剂量阿司匹林已被证明通过抑制HMGB1来预防URSA，而HMGB1反过来又抑制自噬的产生。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

HMGB1 induces unexplained recurrent spontaneous abortion by mediating decidual macrophage autophagy

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HMGB1 induces unexplained recurrent spontaneous abortion by mediating decidual macrophage autophagy

Background

The overexpression of HMGB1 at the maternal-fetal interface (MFI) is recognized as a significant factor in Unexplained Recurrent Spontaneous Abortion (URSA). This study aimed to investigate autophagy in the decidual tissues of URSA patients and to explore the relationship between HMGB1 and macrophage autophagy at the MFI in URSA.

Methods

Human decidual tissues were collected from 40 patients diagnosed with URSA and from 60 women undergoing active termination of pregnancy. Mouse models of pregnancy loss URSA and in vitro cellular models were created and then subjected to treatment with an HMGB1 inhibitor (aspirin) and an anti-HMGB1 antibody, respectively. Autophagy at the MFI was evaluated using western blot analysis, immunofluorescence assays, and transmission electron microscopy (TEM).

Results

This study revealed a high expression of LC3B and a low expression of P62 in the decidual tissue of the URSA group. These findings were further corroborated through TEM. The localization of autophagy within macrophages indicated a significant enhancement of autophagy in the decidual macrophages of the URSA group. However, treatment with low-dose aspirin resulted in a reversal of protein expression and a reduction in autophagy. In in vitro experiments, recombinant HMGB1 was found to mediate autophagy of immortalized bone marrow-derived macrophages, which could be inhibited by an anti-HMGB1 antibody.

Conclusion

This study first indicates that elevated levels of HMGB1 at the MFI trigger autophagy in macrophages, thereby promoting aseptic inflammation and contributing to the onset and progression of URSA. Furthermore, low-dose aspirin has been demonstrated to protect against URSA by inhibiting HMGB1, which in turn suppresses autophagy production.

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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.