Antiphospholipid Antibodies Increase Endometrial Stromal Cell Decidualization, Senescence, and Inflammation via Toll-like Receptor 4, Reactive Oxygen Species, and p38 MAPK Signaling.
Antiphospholipid Antibodies Increase Endometrial Stromal Cell Decidualization, Senescence, and Inflammation via Toll-like Receptor 4, Reactive Oxygen Species, and p38 MAPK Signaling.
复制标题
DOI：
10.1002/art.42068
复制
发表时间：
2022-06
影响因子：
13.3
通讯作者：
Abrahams, Vikki M.
中科院分区：
文献类型：
--
作者：
Tong, Mancy;Kayani, Teimur;Jones, Deidre M.;Salmon, Jane E.;Whirledge, Shannon;Chamley, Lawrence W.;Abrahams, Vikki M.
流产影响七分之一的妊娠，抗磷脂自身抗体（aPL）是复发性流产的最大危险因素之一。虽然aPL靶向子宫内膜基质，但对其影响知之甚少。子宫内膜间质细胞（EnSCs）在每个月经周期经历蜕质化，为子宫接受植入胚胎做好准备。因此，适当的去个体化和EnSC功能是建立成功妊娠的关键。分离条件下的EnSCs暴露于aPL或对照IgG中，或暴露于toll样受体4 （TLR4）拮抗剂、p38 MAPK抑制剂、活性氧（ROS）抑制剂、低分子肝素（LMWH）或乙酰水杨酸（ASA）中。采用酶联免疫吸附试验（ELISA）测定各组细胞中去个性化标志物和炎性白细胞介素(IL)-8的分泌量，并测定衰老相关β-半乳糖苷酶活性。在小鼠脱胎化模型中，给予aPL或对照IgG，并通过RT-qPCR量化子宫脱胎化和炎症标志物的表达。aPL增加人EnSC的去个体化、衰老和炎症。这种表型在小鼠模型中重现。脱醛化和炎症反应部分由TLR4和p38 MAP激酶介导，而脱醛化和衰老反应则依赖于ros。低分子肝素通常用于治疗有产科并发症风险的aPL阳性妇女，它降低了aPL增加EnSC去个体化和炎症的能力。这些发现为aPL妇女妊娠并发症的发病机制提供了新的线索，并强调了肝素在这一高危人群中预防妊娠丢失的益处。
Miscarriage affects one in seven pregnancies and antiphospholipid autoantibodies (aPL) are one of the biggest risk factors for recurrent pregnancy loss. While aPL target the endometrial stroma, little is known about their impact. Endometrial stromal cells (EnSCs) undergo decidualization each menstrual cycle, priming the uterus to receive implanting embryos. Thus, appropriate decidualization and EnSC function is key for establishment of a successful pregnancy. EnSCs under decidualizing conditions were exposed to aPL or control IgG alone or in the presence of either a Toll-like receptor 4 (TLR4) antagonist, a p38 MAPK inhibitor, a reactive oxygen species (ROS) inhibitor, low-molecular weight heparin (LMWH), or acetyl salicylic acid (ASA). Secretion of decidualization markers and inflammatory interleukin (IL)-8 were quantified by ELISA, and senescence-associated β-galactosidase activity was evaluated. In a mouse model of decidualization, aPL or control IgG was administered and uterine expression of decidualization and inflammatory markers quantified by RT-qPCR. aPL increased human EnSC decidualization, senescence and inflammation. This phenotype was recapitulated in the mouse model. The decidualization and inflammatory responses were partially mediated by TLR4 and p38 MAP kinase, while the decidualization and senescence responses were ROS-dependent. LMWH, commonly used to treat aPL-positive women at risk for obstetric complications, reduced the ability of aPL to increase EnSC decidualization and inflammation. These findings shed new light on the pathogenesis of pregnancy complications in women with aPL and underscore the benefit of heparin for preventing pregnancy loss in this high-risk population.
登录
查看更多内容
影响因子：
4.8
作者：
Krikun, G;Mor, G;Lockwood, CJ
通讯作者：
Lockwood, CJ
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
3.9
作者：
Laskin, Carl. A.;Spitzer, Karen A.;Gent, Michael
通讯作者：
Gent, Michael
影响因子：
5.8
作者：
Mak, IYH;Brosens, JJ;White, JO
通讯作者：
White, JO
影响因子：
13.3
作者：
Abrahams, Vikki M.;Chamley, Lawrence W.;Salmon, Jane E.
通讯作者：
Salmon, Jane E.