Frank Pierre, Barrientos Gabriela, Tirado-González Irene, Cohen Marie, Moschansky Petra, Peters Eva M, Klapp Burghard F, Rose Matthias, Tometten Mareike, Blois Sandra M
Laboratory of Reproductive MedicineDepartment of Psychosomatic Medicine and Psychotherapy, Charité Centre 12 Internal Medicine and Dermatology, Medicine University of Berlin, Berlin, GermanyLaboratoire d'HormonologieDepartment of Gynaecology and Obstetrics, Geneva, SwitzerlandDepartment of Psychosomatic MedicinePsycho-Neuro-Immunology, University Giessen, Giessen, GermanyDepartment of Medical OncologyWest German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Laboratory of Reproductive MedicineDepartment of Psychosomatic Medicine and Psychotherapy, Charité Centre 12 Internal Medicine and Dermatology, Medicine University of Berlin, Berlin, GermanyLaboratoire d'HormonologieDepartment of Gynaecology and Obstetrics, Geneva, SwitzerlandDepartment of Psychosomatic MedicinePsycho-Neuro-Immunology, University Giessen, Giessen, GermanyDepartment of Medical OncologyWest German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, GermanyLaboratory of Reproductive MedicineDepartment of Psychosomatic Medicine and Psychotherapy, Charité Centre 12 Internal Medicine and Dermatology, Medicine University of Berlin, Berlin, GermanyLaboratoire d'HormonologieDepartment of Gynaecology and Obstetrics, Geneva, SwitzerlandDepartment of Psychosomatic MedicinePsycho-Neuro-Immunology, University Giessen, Giessen, GermanyDepartment of Medical OncologyWest German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Reproduction. 2014 Aug;148(2):179-89. doi: 10.1530/REP-14-0112. Epub 2014 May 13.
Nerve growth factor (NGF), the first identified member of the family of neurotrophins, is thought to play a critical role in the initiation of the decidual response in stress-challenged pregnant mice. However, the contribution of this pathway to physiological events during the establishment and maintenance of pregnancy remains largely elusive. Using NGF depletion and supplementation strategies alternatively, in this study, we demonstrated that a successful pregnancy is sensitive to disturbances in NGF levels in mice. Treatment with NGF further boosted fetal loss rates in the high-abortion rate CBA/J x DBA/2J mouse model by amplifying a local inflammatory response through recruitment of NGF-expressing immune cells, increased decidual innervation with substance P(+) nerve fibres and a Th1 cytokine shift. Similarly, treatment with a NGF-neutralising antibody in BALB/c-mated CBA/J mice, a normal-pregnancy model, also induced abortions associated with increased infiltration of tropomyosin kinase receptor A-expressing NK cells to the decidua. Importantly, in neither of the models, pregnancy loss was associated with defective ovarian function, angiogenesis or placental development. We further demonstrated that spontaneous abortion in humans is associated with up-regulated synthesis and an aberrant distribution of NGF in placental tissue. Thus, a local threshold of NGF expression seems to be necessary to ensure maternal tolerance in healthy pregnancies, but when surpassed may result in fetal rejection due to exacerbated inflammation.
神经生长因子（NGF）是神经营养因子家族中首个被鉴定出的成员，被认为在应激状态下的怀孕小鼠蜕膜反应启动过程中发挥关键作用。然而，该通路在妊娠建立和维持期间对生理事件的贡献仍 largely 难以捉摸。在本研究中，我们交替使用 NGF 耗竭和补充策略，证明了成功妊娠对小鼠 NGF 水平的干扰很敏感。在高流产率的 CBA/J×DBA/2J 小鼠模型中，通过招募表达 NGF 的免疫细胞放大局部炎症反应、增加 P 物质（+）神经纤维的蜕膜神经支配以及 Th1 细胞因子转变，NGF 治疗进一步提高了胎儿丢失率。同样，在正常妊娠模型 BALB/c 交配的 CBA/J 小鼠中，用 NGF 中和抗体治疗也诱导了流产，这与表达原肌球蛋白激酶受体 A 的 NK 细胞向蜕膜的浸润增加有关。重要的是，在这两种模型中，妊娠丢失均与卵巢功能、血管生成或胎盘发育缺陷无关。我们进一步证明，人类自然流产与胎盘组织中 NGF 的合成上调和异常分布有关。因此，NGF 表达的局部阈值似乎是确保健康妊娠中母体耐受性所必需的，但一旦超过该阈值，可能会因炎症加剧而导致胎儿排斥。
