CD74-downregulation of placental macrophage-trophoblastic interactions in preeclampsia


  • 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


  • Circulation Research


  • Circ Res 119 (1): 55-68


  • 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.