Ákos Heinemann, MD: Leukocyte trafficking, activation and inflammatory mediators
Otto Loewi Research Centre, Division of Pharmacology, Medical University of Graz, Universitätsplatz 4, A-8010 Graz; phone: +43-316-380 4508, fax: +43-316-380 9645, ✉ e-mail
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Keywords:

Research interest:

The main focus of our laboratory is to define the mechanisms that govern the trafficking of leukocytes from bone marrow, where they are generated, to the inflammatory site and their subsequent activation in tissue, where they may become harmful. 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. Conversely, several endogenous mediators exist that down-regulate the responsiveness of leukocytes and might hence exert potent anti-inflammatory effects. When supplemented pharmaceutically, these mediators might likewise open novel therapeutic avenues. 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 decidua 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. We hypothesize that an imbalance of anti-inflammatory PGE₂ effects and pro-inflammatory PGD₂ actions might contribute to complications in pregnancy, such as hypertension, pre-eclampsia or preterm labor. We will characterize these alterations on the cellular (e. g. endothelial cells, macrophages) and tissue level (i. e. placenta).

Illustrations:

Fig. 1: Full-term human placenta stained for D-type prostanoid (DP)1 receptor. The syncytiotrophoblast, surrounding the chorionic villi and forming part of the placental barrier shows strong staining for the DP1 receptor. The arrow indicates a Hofbauer-cell (fetal macrophage) also showing positive staining for DP1. Red asterisks show fetal capillaries inside the villus and the blue asterisk marks the intravillous space (maternal side). Magnification 100× (A) and 600× (B).

Fig. 2: Full-term human placenta stained for D-type prostanoid (DP)2 receptor. The syncytiotrophoblast, surrounding the chorionic villi and forming part of the placental barrier shows staining for the DP2 receptor. The arrow indicates a Hofbauer-cell (fetal macrophage) and the arrowhead points to a fetal leukocyte inside a capillary, both showing positive staining for DP2. Red asterisks show fetal capillaries inside the villus and the blue asterisk marks the intravillous space filled with maternal erythrocytes (maternal side). Magnification 100× (A) and 600× (B).

References:

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):100–109.
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.
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 receptor prevents acute lung injury in mice by enhancing the microvascular barrier function. Br J Pharmacol, 2015; 172(18):4454–4468.
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.
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.

Collaborations within the DP-iDP:

• G. Desoye will teach the students how to isolate endothelial cells and macrophages from the placenta and / or umbilical cord, introduce them to the biology of angiogenesis and help with assays of 2-D network formation and tube formation.
• G. Marsche will supervise the studies addressing lipid metabolism of placental macrophages.
• C. Wadsack will provide clinically well-defined placenta samples and help the students with ex vivo placenta perfusion assays.
• In studies conducted by M. van Poppel the students will learn how to measure and statistically analyze cytokine plasma profiles in normal and pathological pregnancies.

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

• S. E. Dahlen (Karolinska Institutet, Stockholm, Sweden) is an expert in prostaglandin biology and will facilitate the mass spectrometric analysis of eicosanoids and endocannabinoids generated in vivo and in vitro.
• E. Kostenis (University of Bonn, Germany) is a molecular pharmacologist in the field of eicosanoid receptors. She will train the students in heterologous expression of prostanoid receptors and characterization of ligands in binding studies and second messenger signaling including assays of dynamic mass redistribution.
• B. Lindenthal (Bayer Pharma, Berlin, Germany) is an industrial pharmacologist who will introduce the students to the drug development program and the methods employed by Bayer in the field of prostaglandin antagonists for the treatment of gynecological disorders.

Industrial partners:

Know-how and infrastructure of the research group:

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

28.05.2018 DP-iDP Doctoral Programme “Inflammatory Disorders in Pregnancy”