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CD74-Downregulation of Placental Macrophage-Trophoblastic Interactions in Preeclampsia
Lukasz Przybyl1, Nadine Haase1, Michaela Golic1
1From the Experimental and Clinical Research Center, A Joint Cooperation Between the Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M. Golic, J.R., F.C.L., D.N.M., R.D., F.H.); Berlin Institute of Health (BIH), Berlin, Germany (L.P., N.H., M. Golic, J.R., D.N.M., R.D., F.H.); Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.H., H.S., A.H., F.C.L., D.N.M., F.H.); Departments of Obstetrics, Gynecology, and Senology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany (M. Golic); Department of Obstetrics and Fetal Medicine, Laboratory for Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (M.E.S., P.C.A.); Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria (M. Gauster, B.H.); Institute of Biochemistry and Molecular Cell Biology (C.E., C.S., J.B.) and Department of Anesthesiology (C.S.), RWTH Aachen University, Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (J.B.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (J.B.); Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (L.L., R.B.); Cologne Center for Genomics (CCG), University of Cologne, Köln, Germany (H.S.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Ulleval, Norway (M.S.W.-F., G.M.J., A.C.S.); University of Oslo, Oslo, Norway (M.S.W.-F., G.M.J., A.C.S.); and HELIOS-Klinikum, Berlin, Germany (D.P., R.D.).
Rationale:
We 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 reverse transcriptase-polymerase chain reaction, 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 with 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 with controls. CD74-silenced macrophages showed that the adhesion molecules ALCAM, ICAM4, and Syndecan-2, as well as macrophage adhesion to trophoblasts were diminished. Naive and activated macrophages lacking CD74 showed a shift toward a proinflammatory signature with an increased secretion of tumor necrosis factor-α, chemokine (C-C motif) ligand 5, and monocyte chemotactic protein-1, when cocultured with trophoblasts compared with 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.
Conclusions:
CD74 downregulation in placental macrophages is present in preeclampsia. CD74 downregulation leads to altered macrophage activation toward a proinflammatory signature and a disturbed crosstalk with trophoblasts.
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