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Medizinische Universität Graz

PI, Heinemann

Leukocyte trafficking, activation and inflammatory mediators

Pregnancy is an immunological challenge for mother and fetus, and numerous immune cells take part in the development of the placenta. Particularly macrophages are thought to be crucial in maintaining an immune-tolerant environment in the semi-allogeneic setting of trophoblast invasion (1). Chemoattractants, their receptors, and adhesion molecules both on the leukocytes and the endothelial side, play crucial roles in the multi-step process of leukocyte infiltration by facilitating leukocyte locomotion and activation, and are thus considered as promising therapeutic targets in various inflammatory conditions. Among others we have elucidated the opposing roles of two cyclooxygenase (COX) products, prostaglandin (PG) E2 and D2 in leukocyte trafficking in human and animal models, and have characterized their receptors at the molecular and pharmacological level. While we have shown that its receptor EP4 is a negative regulator of eosinophil and neutrophil trafficking, and endothelial, thrombocyte and macrophage activation (2, 3), we have also revealed a novel role for PGD2 and its receptors DP1 and DP2 as potent activators of eosinophils, basophils and macrophages (4, 5). It has been suggested previously that PGE2 and PGD2 might play distinct roles in pathological conditions of pregnancy, but how these prostaglandins contribute to the regulation of leukocyte function in the developing placenta and, even more, how responses to PGE2 and PGD2 of immune cells in the placenta are altered in different gestational pathologies has not been addressed in detail. Currently we are elucidating the expression patterns and levels of enzymes involved in prostaglandin synthesis (COX isoforms, PGE and PGD synthases) and receptors for PGE2 and PGD2 in placental tissue (CW, GD). We hypothesize that an imbalance of anti-inflammatory PGE2 effects and pro-inflammatory PGD2 actions might contribute to complications in pregnancy, such as hypertension, preeclampsia or preterm labor. We will characterize these alterations on the cellular (e.g. endothelial cells, macrophages) and placental tissue Level.

1. Svensson-Arvelund J, Ernerudh J. The role of macrophages in promoting and maintaining homeostasis at the fetal-maternal interface. Am J Reprod Immunol. 2015;74(2):100-9. doi: 10.1111/aji.12357.

2. Konya V, Marsche G, Schuligoi R, Heinemann A. E-type prostanoid receptor 4 (EP4) in disease and therapy. Pharmacol Ther. 2013;138(3):485-502. doi: 10.1016/j.pharmthera.2013.03.006.

3. Konya V, Maric J, Jandl K, Luschnig P, Aringer I, Lanz I, Platzer W, Theiler A, Bärnthaler T, Frei R, Marsche G, Marsh LM, Olschewski A, Lippe IT, Heinemann A, Schuligoi R. Activation of EP4 receptors prevents endotoxin-induced neutrophil infiltration into the airways and enhances microvascular barrier function. Brit J Pharmacol. 2015;172(18):4454-4468. doi: 10.1111/bph.13229.

4. Schuligoi R, Sturm E, Luschnig P, Konya V, Philipose S, Sedej M, Waldhoer M, Peskar BA, Heinemann A. CRTH2 and D-type prostanoid receptor antagonists as novel therapeutic agents for inflammatory diseases. Pharmacology. 2010;85(6):372-382. doi: 10.1159/000313836.

5. Jandl K, Stacher E, Bálint Z, Sturm EM, Maric J, Peinhaupt M, Luschnig P, Aringer I, Fauland A, Konya V, Dahlen SE, Wheelock CE, Kratky D, Olschewski A, Marsche G, Schuligoi R, Heinemann A. Activated prostaglandin D2 receptors on macrophages enhance neutrophil recruitment into the lung. J Allergy Clin Immunol. 2016;137(3):833-843. doi: 10.1016/j.jaci.2015.11.012.

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