Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Jandl, K.
Role of Prostaglandin D2 Receptors in Monocyte/Macrophage Function in Pulmonary Inflammation
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2016. pp.
[OPEN ACCESS]
FullText
- Autor*innen der Med Uni Graz:
- Jandl Katharina
- Betreuer*innen:
- Heinemann Akos
- Kratky Dagmar
- Olschewski Andrea
- Altmetrics:
- Abstract:
- Prostaglandin (PG) D2 is released during the early-phase of inflammation. This lipid mediator exerts its bioactive potential via its two D-type prostanoid (DP) receptors, DP1 and DP2 (also called CRTH2 for chemoattractant receptor homologous molecule expressed on Th2 cells). Both receptors are reported to be associated with distinct biological effects, DP2 being clearly proinflammatory, while the role of DP1 in inflammation has still remained unclear. Up to now, the potential of PGD2 in the regulation of macrophage function and its role in the early phase of experimental acute lung-injury has not been elucidated yet. Here, we could show for the first time that human monocyte-derived macrophages express functional PGD2 receptors. Activation of either PGD2 receptors led to intracellular Ca2+ signaling that resulted in migration of macrophages. In contrast, stimulation of DP2, but not DP1 induced cytokine release in a NF¿B-dependent fashion. These proinflammatory effects were transferable to in-vivo responses during the early phase of LPS-induced acute lung injury in mice. PGD2 treatment, as well as the specific activation of either DP1 or DP2 receptors, led to aggravated pulmonary inflammation visible by increased neutrophilic alveolitis, myeloperoxidase activity and airway hyperreactivity in lung function testing. Alveolar macrophages could be identified as a driving source of increased cytokine secretion upon exogenous PGD2 treatment and depletion of alveolar macrophages proved to inhibit the augmented inflammatory reactions caused by PGD2. Furthermore, blockade of endogenous PGD2 diminished neutrophil recruitment into both alveolar and pulmonary interstitial space. Most importantly, we could identify neutrophil migration and survival as two pathways in which activation of PGD2 receptors on macrophages influences neutrophil function. Interestingly, we detected the presence of the hematopoietic prostaglandin D synthase (HPGDS) – the rate-limiting enzyme of PGD2 production –and the receptors for PGD2 on alveolar macrophages in humans. The increased expression of HPGDS in the lungs of patients with acute-respiratory distress syndrome suggests an autocrine feed-back loop of HPGDS-PGD2-DP1-DP2 action on macrophages. This study extents the existing knowledge of PGD2 pharmacology and action on immune cells by showing the presence and functionality of PGD2 receptors on human monocyte-derived macrophages. Activation of the latter increased pulmonary inflammation by enhancing neutrophil function. Thus PGD2 receptors on macrophages might prove a potential therapeutic target during acute inflammatory pulmonary diseases.