CD74-Downregulation of Placental Macrophage-Trophoblastic Interactions in Preeclampsia
Circulation Research. 2016 May 19. pii: CIRCRESAHA.116.308304. DOI: 10.1161/CIRCRESAHA.116.308304. [Epub ahead of print]
|Authors/Editors:||Przybyl L, Haase N, Golic M, Rugor J, Solano M E, Arck P C, Gauster M, Huppertz B, Emontzpohl C, Stoppe C, Bernhagen J, Leng L, Bucala R, Schulz H, Heuser A, Weedon-Fekjær M S, Johnson G M, Peetz D, Luft F C, Staff A C, Müller D N, Dechend R, Herse F.|
We hypothesized that Cluster of differentiation 74 (CD74) downregulation on placental macrophages, leading to altered macrophage-trophoblast interaction, is involved in preeclampsia.
Preeclamptic pregnancies feature hypertension, proteinuria and placental anomalies. Fetoplacental 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 proinflammatory signature with an increased secretion of TNFα, CCL5, and MCP-1, when co-cultured with trophoblasts compared to control macrophages. Trophoblasts stimulated by these factors express more CYP2J2, sFlt1, TNFα and IL-8. CD74-knockout mice showed disturbed placental morphology, reduced junctional zone, smaller placentas and impaired spiral artery remodeling with fetal growth restriction.
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.