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Martin Gauster, PhD:

Placenta-derived cytokines and chemokines in maternal leukocyte activation

Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Chair of Cell Biology, Histology and Embryology, Medical University of Graz, Neue Stiftingtalstraße 6/II, A-8010 Graz;
phone: +43-316-385 71896, fax: +43-316-380 79612, ✉ e-mail
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Keywords:

Placenta, inflammation, cytokines, chemokines, maternal-fetal cell interaction, maternal leukocyte activation

Research interest:

Hemochorial placentation, with placental villi bathing in maternal blood, entails direct contact of circulating maternal leukocytes with the fetal trophoblast, i. e. the syncytiotrophoblast, which covers all placental villous trees as well as parts of the inner surfaces of chorionic and basal plates (1). This way, placenta-derived factors, such as hormones and cytokines predominantly released by the syncytio-trophoblast, may influence circulating maternal blood cells and vice versa factors from maternal leukocytes may regulate villous trophoblast functions. Thus, a combination of modulating signals and responses between maternal circulating blood cells and the placental trophoblast may dynamically be adjusted over gestation for an overall cooperative microenvironment in the intervillous space. Alterations in this cooperative microenvironment may occur very early in pregnancy and is suggested to program early placenta functions and growth long before any phenotypic changes become clinically apparent (2).

We recently identified the unique chemokine fractalkine at the apical microvillous plasma membrane of the syncytiotrophoblast of human first-trimester and term placenta, from where it can be released into maternal circulation by constitutive metalloprotease-dependent shedding (3). Membrane-bound fractalkine, expressed in differentiated villous trophoblasts, mediates adherence of CX3CR1 expressing THP-1 monocytes (4). Expression of placental fractalkine is upregulated by tumor necrosis factor (TNF)-α through activation of NF-κB p65 and is upregulated in placentas from pregnancies complicated by severe early onset preeclampsia (5). Additionally, our recent studies suggest that increased maternal TNF-α levels substantially alter the secretion profile of inflammation-associated factors in human first trimester villous placenta. Conditioned culture media from TNF-α-treated first-trimester villous placental explants showed increased secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF), CCL5, and IL-10, whereas IL-4 and macrophage colony-stimulating factor (M-CSF) levels decreased compared with controls (6). In a follow-up study we showed considerable levels of CXCL4 in placental explant homogenates and corresponding conditioned culture media (7). Immunohistochemistry localized GM-CSF in the villous trophoblast compartment, whereas CCL5 and CXCL4 were detected in maternal platelets adhering to perivillous fibrin deposits, suggesting the latter as important cytokine and chemokine source for the intervillous microenvironment.

Our observations suggest that the placental cytokine / chemokine secretion profile can be altered by maternal circulating immune-modulating factors, which in turn may affect interaction of the fetal trophoblast with passing maternal blood cells.

Illustrations:

Fig. 1: Immunohistochemistry micrograph of maternal monocyte interaction with fetal trophoblast.

References:

  1. Benirschke K, Kaufmann P, Baergen RN: Pathology of the Human Placenta. Springer: New York, NY, 5th edn. 2006, ISBN 978-0-387-26738-8, pp. 42–49.
  2. Catalano P, deMouzon SH: Maternal obesity and metabolic risk to the offspring: why lifestyle interventions may have not achieved the desired outcomes. Int J Obes (Lond), 2015; 39(4):642–649.
  3. Siwetz M, Blaschitz A, Kremshofer J, Bilic J, Desoye G, Huppertz B, Gauster M: Metalloprotease dependent release of placenta derived fractalkine. Mediators Inflamm, 2014; 2014:839290.
  4. Siwetz M, Sundl M, Kolb D, Hiden U, Herse F, Huppertz B, Gauster M: Placental fractalkine mediates adhesion of THP-1 monocytes to villous trophoblast. Histochem Cell Biol, 2015;143(6):565–574.
  5. Siwetz M, Dieber-Rotheneder M, Cervar-Zivkovic M, Kummer D, Kremshofer J, Weiss G, Herse F, Huppertz B, Gauster M: Placental fractalkine is up-regulated in severe early-onset preeclampsia. Am J Pathol, 2015; 185(5):1334–1343.
  6. Siwetz M, Blaschitz A, El-Heliebi A, Hiden U, Desoye G, Huppertz B, Gauster M: TNF-α alters the inflammatory secretion profile of human first trimester placenta. Lab Invest, 2016; 96(4):428–438.
  7. Blaschitz A, Siwetz M, Schlenke P, Gauster M: Adhering maternal platelets can contribute to the cytokine and chemokine cocktail released by human first trimester villous placenta. Placenta, 2015; 36(11):1333–1336.

Collaborations within the DP-iDP:

  • G. Desoye introduce students to the biology of placenta development and processes of early placenta inflammation. Moreover, he will provide primary trophoblasts isolated from human first trimester and term placenta.
  • Á. Heinemann will support students in leukocyte adhesion- and activation assays.
  • C. Wadsack will support students with ex vivo placenta perfusion and will provide placenta perfusates for placenta derived cytokine / chemokine profiling.

Collaborating research groups where PhD students could perform their research stay abroad:

  • F. Herse (Max-Delbrueck Center for Molecular Medicine (MDC) and Experimental and Clinical Research Center (ECRC); Berlin, Germany) focuses on preeclampsia, reproductive immunology and the renin–angiotensin system. Moreover, Dr. Herse has expertise in rat models for pregnancy disorders such as preeclampsia and intrauterine growth restriction. He will teach the students in experimental animal handling.

Know-how and infrastructure of the research group:

Dr. Gauster’s research laboratory is equipped for standard molecular biological and biochemical protocols such as western blotting, qPCR, PAGE, DELFIA and ELISA. Moreover, the institute provides expert knowledge in cell biological and histological techniques. Dr. Gauster has access to state-of-the-art microscopes (e. g. inverse fluorescence microscope, confocal laser scanning microscope, electron microscope) and efficient software tools to obtain stereology based quantities. Available cell culture devices exceed basic equipment (e. g. hypoxia workstation and live-cell imaging). Tissue specimens will be fixed and embedded routinely by an in-house paraffin infiltration processor and immunohistochemical staining of tissue sections will be performed by a staining robot (autostainer).

Scientific concepts and techniques that students will learn in this laboratory:

DP-iDP students will be trained in cell- and tissue-culture techniques, including isolation and culture of primary trophoblasts, maternal blood cells and preparation of placental tissue explants. Moreover, students will obtain skills in state-of-the-art downstream analyses methods, such as qPCR, western blots, immunohistochemistry and ELISA. Besides wet-laboratory approaches, students will get background knowledge on placenta development and insight into underlying mechanisms involved in early placenta inflammation.

29.05.2018 DP-iDP Doctoral Programme “Inflammatory Disorders in Pregnancy”