Balanced levels of nerve growth factor are required for normal pregnancy progression.
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.
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.
Pierre
P
Frank
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.
Gabriela
G
Barrientos
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.
Irene
I
Tirado-González
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.
Marie
M
Cohen
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.
Petra
P
Moschansky
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.
Eva M
EM
Peters
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.
Burghard F
BF
Klapp
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.
Matthias
M
Rose
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.
Mareike
M
Tometten
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 sandra.blois@charite.de.
Sandra M
SM
Blois
D000022:Abortion, Spontaneous / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003656:Decidua / Q000166:cytology / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005327:Fetal Resorption / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010920:Placenta / Q000166:cytology / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism*
C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D020932:Nerve Growth Factor; D020917:Receptor, trkA