CD74-Downregulation of Placental Macrophage-Trophoblastic Interactions in Preeclampsia
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CD74-Downregulation of Placental Macrophage-Trophoblastic Interactions in Preeclampsia. / Przybyl, Lukasz; Haase, Nadine; Golic, Michaela; Rugor, Julianna; Solano, Maria E; Arck, Petra C; Gauster, Martin; Huppertz, Berthold; Emontzpohl, Christoph; Stoppe, Christian; Bernhagen, Juergen; Leng, Lin; Bucala, Richard; Schulz, Herbert; Heuser, Arnd; Weedon-Fekjaer, Susanne; Johnsen, Guro M; Peetz, Dirk; Luft, Friedrich C; Staff, Anne Cathrine; Mueller, Dominik N; Dechend, Ralf; Herse, Florian.
in: CIRC RES, Jahrgang 119, Nr. 1, 19.05.2016, S. 55-68.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - CD74-Downregulation of Placental Macrophage-Trophoblastic Interactions in Preeclampsia
AU - Przybyl, Lukasz
AU - Haase, Nadine
AU - Golic, Michaela
AU - Rugor, Julianna
AU - Solano, Maria E
AU - Arck, Petra C
AU - Gauster, Martin
AU - Huppertz, Berthold
AU - Emontzpohl, Christoph
AU - Stoppe, Christian
AU - Bernhagen, Juergen
AU - Leng, Lin
AU - Bucala, Richard
AU - Schulz, Herbert
AU - Heuser, Arnd
AU - Weedon-Fekjaer, Susanne
AU - Johnsen, Guro M
AU - Peetz, Dirk
AU - Luft, Friedrich C
AU - Staff, Anne Cathrine
AU - Mueller, Dominik N
AU - Dechend, Ralf
AU - Herse, Florian
PY - 2016/5/19
Y1 - 2016/5/19
N2 - 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.
AB - 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.
U2 - 10.1161/CIRCRESAHA.116.308304
DO - 10.1161/CIRCRESAHA.116.308304
M3 - SCORING: Journal article
C2 - 27199465
VL - 119
SP - 55
EP - 68
JO - CIRC RES
JF - CIRC RES
SN - 0009-7330
IS - 1
ER -