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Nerve Growth Factor Translates Stress Response and Subsequent Murine Abortion via Adhesion Molecule-Dependent Pathways¹

Charité, Universitätsmedizin Berlin, Joint Institution of the Freie Universität and Humboldt Universität, Biomedical Research Center, Campus Virchow, 13353 Berlin, Germany

ABSTRACT

Spontaneous abortion is a frequent threat affecting 10%–25% of human pregnancies. Psychosocial stress has been suggested to be attributable for pregnancy losses by challenging the equilibrium of systems mandatory for pregnancy maintenance, including the nervous, endocrine, and immune system. Strong evidence indicates that stress-triggered abortion is mediated by adhesion molecules, i.e., intercellular adhesion molecule 1 (ICAM1) and leukocyte function associated molecule 1, now being referred to as integrin alpha L (ITGAL), which facilitate recruitment of inflammatory cells to the feto-maternal interface. The neurotrophin beta-nerve growth factor (NGFB), which has been shown to be upregulated in response to stress in multiple experimental settings including in the uterine lining (decidua) during pregnancy, increases ICAM1 expression on endothelial cells. Here, we investigated whether and how NGFB neutralization has a preventive effect on stress-triggered abortion in the murine CBA/J x DBA/2J model. We provide experimental evidence that stress exposure upregulates the frequency of abortion and the expression of uterine NGFB. Further, adhesion molecules ICAM1 and selectin platelet (SELP, formerly P-Selectin) and their ligands ITGAL and SELP ligand (SELPL, formerly P selectin glycoprotein ligand 1) respectively increase in murine deciduas in response to stress. Subsequently, decidual cytokines are biased toward a proinflammatory and abortogenic cytokine profile. Additionally, a decrease of pregnancy protective CD8⁺ decidual cells is present. Strikingly, all such uterine stress responses are abrogated by NGFB neutralization. Hence, NGFB acts as a proximal mediator in the hierarchical network of immune rejection by mediating an abortogenic environment comprised of classical signs of neurogenic inflammation.

female reproductive tract, immunology, pregnancy, neuropeptides, stress

¹ Supported by grants from the Charité to M.T., S.B., and P.A.; S.B. received a scholarship from the Schering Research Foundation. S.B., M.T., and P.A. are part of the EMBIC Network of Excellence, cofinanced by the European Commission through the FP6 framework program "Life Science, Genomics and Biotechnology for Health."

² Correspondence: Petra Clara Arck, Biomedizinisches Forschungszentrum, Raum 2.0549, Augustenburger Platz 1, 13353 Berlin, Germany. FAX: 49 30 450 553962; petra.arck{at}charite.de

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