Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Rittchen, S.
The hPGDS-PGD2-DP1-DP2 axis in innate immunity and pulmonary inflammation
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2021. pp.
- Autor*innen der Med Uni Graz:
- Rittchen Sonja
- Betreuer*innen:
- Desoye Gernot
- Heinemann Akos
- Kwapiszewska-Marsh Grazyna
- Altmetrics:
- Abstract:
- Respiratory diseases pose a great burden on public health and are among the leading causes of death and disability worldwide. It has now been widely accepted that innate immunity, at its centre alveolar macrophages, plays a pivotal role in modulating pulmonary inflammation. To-date, we still lack specific targets to limit hyper-activation or aberrant function of innate immunity. Prostaglandin (PG) D2 is a potent lipid mediator exerting various inflammatory actions including recruitment and activation of immune cells, broncho-constriction and airway hyper-reactivity. Due to this, there has been immense interest in limiting PGD2 production and signalling to alleviate pulmonary inflammation, especially for patients suffering from allergic asthma. Yet, PGD2-induced effects have proven to be more complex than previously thought. Its action depends on many factors, thereby further complicating a definite functional classification. On these grounds, this PhD thesis is dedicated to expanding the knowledge about PGD2-elicited effects in the context of pulmonary inflammation. In the first part of this thesis, we found that PGD2 and the DP1 agonist BW245c potently increased pulmonary and dermal microvascular endothelial cell barrier function and protected against thrombin-induced barrier disruption. Surprisingly, these effects were mediated only to a minor extent through DP1 receptor activation and were independent from cAMP/PKA activation, as it has been previously published for DP1-related barrier enhancement. In contrast, we could prove that EP4 receptor activation was pivotal for barrier enhancement by PGD2 and BW245c. These data demonstrate a novel mechanism by which PGD2 may modulate pulmonary inflammation and emphasizes the role of EP4 receptors in human endothelial cell function. Mast cells are believed to be the primary PGD2 sources; however, their involvement in acute inflammation is rather unlikely due to their low numbers in non-allergic settings. In the second part of this thesis, we evaluated the potential of monocytes and macrophages as prostaglandin sources in vitro as well as in murine models of lung inflammation. Remarkably, PGD2 and PGE2 release by human monocytes significantly surpassed the levels observed for monocyte-derived macrophages after LPS/IFN-γ stimulation. In vivo data confirmed that monocytes and macrophages act as potent PG source and are capable of contributing to elevated PGD2 levels in acute pulmonary inflammation, but not allergic inflammation. Further investigation will be necessary to delineate how to exploit the therapeutic potential of this finding. In the third part, we explored the role of DP2 receptor activation on macrophages and their regenerative function, i.e. the formation of new vessels. Macrophages not only influence the early phase of inflammation but also actively participate in the regeneration of epithelial and endothelial layers, which is a critical step towards restored lung function. We found that DP2 receptor activation on IL-4 polarized human monocyte-derived macrophages reduced sprout formation of human pulmonary microvascular endothelial cells and angiogenesis in the chicken CAM assay. Deregulated angiogenesis and resulting vascular dysfunction often contribute to airway and tissue remodelling, thus, posing a promising therapeutic approach to ameliorate acute and chronic airway inflammation. Summing up, these data clarify some of the vast functions of PGD2 on the innate immune system including the novel findings that i) PGD2 is able to act through EP4 receptor activation, ii) monocytes release significant levels of PGD2 and iii) PGD2-DP2 signalling on macrophages modulates their angiogenic potential. Further investigation is required to explore the therapeutic relevance of these findings, but this knowledge will be valuable in the future to develop targeted anti-inflammatory or regenerative therapies for respiratory diseases.