Przybyl, Lukasz ORCID: 0000-0001-9777-8879, Haase, Nadine ORCID: 0000-0003-0727-1738, Golic, Michaela ORCID: 0000-0003-3030-2678, Rugor, Julianna, Solano, Maria Emilia, Arck, Petra Clara, Gauster, Martin ORCID: 0000-0003-0386-6857, Huppertz, Berthold ORCID: 0000-0003-4814-2158, Emontzpohl, Christoph, Stoppe, Christian ORCID: 0000-0002-2028-2039, Bernhagen, Juergen, Leng, Lin ORCID: 0000-0002-0605-358X, Bucala, Richard, Schulz, Herbert, Heuser, Arnd ORCID: 0000-0002-3334-960X, Weedon-Fekjr, M. Susanne, Johnsen, Guro M., Peetz, Dirk, Luft, Friedrich C., Staff, Anne Cathrine, Mueller, Dominik N., Dechend, Ralf and Herse, Florian ORCID: 0000-0002-9305-8134 (2016). CD74-Downregulation of Placental Macrophage-Trophoblastic Interactions in Preeclampsia. Circ.Res., 119 (1). S. 55 - 93. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1524-4571

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Abstract

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-a, 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, TNF alpha, 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Przybyl, LukaszUNSPECIFIEDorcid.org/0000-0001-9777-8879UNSPECIFIED
Haase, NadineUNSPECIFIEDorcid.org/0000-0003-0727-1738UNSPECIFIED
Golic, MichaelaUNSPECIFIEDorcid.org/0000-0003-3030-2678UNSPECIFIED
Rugor, JuliannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Solano, Maria EmiliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arck, Petra ClaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gauster, MartinUNSPECIFIEDorcid.org/0000-0003-0386-6857UNSPECIFIED
Huppertz, BertholdUNSPECIFIEDorcid.org/0000-0003-4814-2158UNSPECIFIED
Emontzpohl, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoppe, ChristianUNSPECIFIEDorcid.org/0000-0002-2028-2039UNSPECIFIED
Bernhagen, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leng, LinUNSPECIFIEDorcid.org/0000-0002-0605-358XUNSPECIFIED
Bucala, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulz, HerbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heuser, ArndUNSPECIFIEDorcid.org/0000-0002-3334-960XUNSPECIFIED
Weedon-Fekjr, M. SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Johnsen, Guro M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peetz, DirkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luft, Friedrich C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Staff, Anne CathrineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, Dominik N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dechend, RalfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herse, FlorianUNSPECIFIEDorcid.org/0000-0002-9305-8134UNSPECIFIED
URN: urn:nbn:de:hbz:38-272049
DOI: 10.1161/CIRCRESAHA.116.308304
Journal or Publication Title: Circ.Res.
Volume: 119
Number: 1
Page Range: S. 55 - 93
Date: 2016
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Place of Publication: PHILADELPHIA
ISSN: 1524-4571
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MIGRATION INHIBITORY FACTOR; NECROSIS-FACTOR-ALPHA; INVARIANT CHAIN; TOXOPLASMA-GONDII; NORMAL-PREGNANCY; HOFBAUER CELLS; IFN-GAMMA; EXPRESSION; CD74; MIFMultiple languages
Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular DiseaseMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/27204

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