124. Immune-driven polyunsaturated fatty acid (PUFA) metabolism in preeclampsia

Abstract

Introduction Placental macrophages regulate villous trophoblast differentiation and activity. Disturbance of this well-balanced immune-regulation and a pro-inflammatory cytokine milieu can lead to dysfunctional placentas and preeclampsia. Cluster of differentiation 74 (CD74) downregulation in placental macrophages leads to altered macrophage-trophoblast interaction, a pro-inflammatory status and is involved in preeclampsia. Oxylipins, metabolites derived from polyunsaturated fatty acids (PUFAs), are implicated in the development of preeclampsia. Hypothesis Disturbed pro-inflammatory cytokine milieu activates a dysregulated PUFA metabolism enzyme expression pattern leading to disturbed oxylipin levels that can be detected in circulation of preeclamptic mothers. Methods A trophoblast-derived cell line (SGHPL-4) and first trimester villous explants were stimulated by the pro-inflammatory cytokines TNFa, CCL5 and MCP-1. Furthermore, we analyzed placental expression pattern of cytochrome P450 epoxygenases, cyclooxygenases and lipoxygenases by microarray and qRT-PCR from human cohorts and analyzed serum from preeclamptic and uneventful pregnancies by mass spectrometry. Results Microarray studies of preeclamptic placentas revealed a distinguished expression pattern of PUFA metabolism enzymes. Results could be confirmed on two different cohorts (qRT-PCR). Stimulation of SGHPL-4 and villous explants by the pro-inflammatory cytokines TNFa, CCL5 and MCP-1 resulted in similar expression pattern. Oxylipins were dysregulated in the circulation of preeclamptic women compared to uneventful pregnancies atgestational week 28 and week 9–12. Composition of oxylipins at week 9–12 in women that later develop preeclampsia showed a good ROC predictive performance with an AUC = 0.8. Conclusion The pro-inflammatory cytokine milieu induced by the disturbed macrophage-trophoblast interaction induces a distinguished PUFA metabolism leading to dysregulated oxylipins that can predict preeclampsia before onset of clinical symptoms.