CD74-downregulation of placental macrophage-trophoblastic interactions in preeclampsia
Autor/innen
- L. Przybyl
- N. Haase
- M. Golic
- J. Rugor
- M.E. Solano
- P.C. Arck
- M. Gauster
- B. Huppertz
- C. Emontzpohl
- C. Stoppe
- J. Bernhagen
- L. Leng
- R. Bucala
- H. Schulz
- A. Heuser
- S. Weedon-Fekjær
- G.M. Johnsen
- D. Peetz
- F.C. Luft
- A.C. Staff
- D.N. Müller
- R. Dechend
- F. Herse
Journal
- Circulation Research
Quellenangabe
- Circ Res 119 (1): 55-68
Zusammenfassung
Rationale: MWe hypothesized that Cluster of differentiation 74 (CD74) downregulation on placental macrophages, leading to altered macrophage-trophoblast interaction, is involved in preeclampsia. Objective: Preeclamptic pregnancies feature hypertension, proteinuria and placental anomalies. Feto-placental macrophages regulate villous trophoblast differentiation during placental development. Disturbance of this well-balanced regulation can lead to pathological pregnancies. Methods and Results: We performed whole genome expression analysis of placental tissue. CD74 was one of the most downregulated genes in placentas from preeclamptic women. By RT-PCR, we confirmed this finding in early onset (<34 gestational week, n=26) and late onset (≥34 gestational week, n=24) samples from preeclamptic women, compared to healthy pregnant controls (n=28). CD74 protein levels were analyzed by Western blot and flow cytometry. We identified placental macrophages to express CD74 by immunofluorescence, flow cytometry and RT-PCR. CD74-positive macrophages were significantly reduced in preeclamptic placentas compared to controls. CD74-silenced macrophages showed that the adhesion molecules ALCAM, ICAM4, and Syndecan-2, as well as macrophage adhesion to trophoblasts were diminished. Naïve and activated macrophages lacking CD74 showed a shift towards a pro-inflammatory signature with an increased secretion of TNF , CCL5, and MCP-1, when co-cultured with trophoblasts compared to control macrophages. Trophoblasts stimulated by these factors express more CYP2J2, sFlt1, TNF and IL-8. CD74-knockout mice showed disturbed placental morphology, reduced junctional zone, smaller placentas and impaired spiral artery remodeling with fetal growth restriction. Conclusions: CD74 downregulation in placental macrophages is present in preeclampsia. CD74 downregulation leads to altered macrophage activation towards a pro-inflammatory signature and a disturbed crosstalk with trophoblasts.