Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Roula, D.
Elucidating the possible Relation between Apolipoprotein A-IV and Prostaglandin D2 in Cells involved in the Pathogenesis of Allergic Asthma and Rheumatoid Arthritis.
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2020. pp. 148
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Böhm Eva
- Heinemann Akos
- Stradner Martin Helmut
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- Abstract:
- In the western world, allergies and autoimmune diseases are on the rise, including allergic asthma and rheumatoid arthritis (RA), respectively. Understanding how these pathologies develop is vital in the search for a cure. In recent years, a body of evidence accumulated that linked dysregulations in the immune system to dysregulations of metabolism. In both allergic asthma and rheumatoid arthritis, altered levels of apolipoproteins have been observed. Apolipoproteins are proteins present on the surface of lipoproteins and have long been considered to exclusively regulate lipid metabolism. Apolipoprotein A-IV (ApoA-IV) is a 46 kDa amphipathic protein present on chylomicrons, very low-density lipoproteins and in plasma. Its physiologic function has not been illuminated yet, but reports started to emerge that point to anti-inflammatory properties. ApoA-I, an apolipoprotein that is structurally related to ApoA-IV, has been shown to induce production of prostaglandin D2 (PGD2) in vitro. In both diseases, elevated levels of PGD2 are present at the site of inflammation. PGD2, an arachidonic acid-derived lipid mediator, possesses both pro- and anti-inflammatory properties, mediated through two surface receptors called DP1 and DP2. Receptor expression is widely distributed among leukocytes but also tissue cells. The aim of this study was to elucidate a possible relation between ApoA-IV and PGD2 in the context of allergic asthma and RA. To achieve this, a flow cytometric approach was used to test the effect of ApoA-IV on eosinophil and monocyte migration, macrophage polarization and neutrophil activation. In a small clinical cohort, we assessed DP2 receptor expression in leukocytes of patients suffering from RA. Western blot, quantitative RT-PCR and ELISA assays were used to measure protein expression, mRNA expression and cytokine production of the nuclear receptor NR1D1, prostaglandin synthases mPGES-1 and hPGDS and cytokines TNF-α and IL-10 respectively. RIA and ELISA were performed to measure production of prostaglandin E2 and D2. Murine models of airway hypersensitivity and experimental arthritis were used to measure the impact of ApoA-IV and DP2 antagonist OC000459 in vivo on pathophysiology, respectively. We show that ApoA-IV potently suppresses eosinophil chemotaxis in vitro via NR1D1 and improves lung inflammation and pulmonary function in vivo. We show further that ApoA-IV potently suppresses monocyte activation, chemotaxis and induces PGE2 production. In macrophages, ApoA-IV potently suppresses the pro-inflammatory M1 phenotype by decreasing surface expression of CD80 and production of TNF-α. The observed reduction of CD80 is mediated through NR1D1. In patients suffering from rheumatoid arthritis, we show that plasma ApoA-IV is decreased and that DP2 expression is reduced ex vivo monocytes and increased in basophils compared to healthy donors. Monocyte-derived M2 macrophages differentiated in vitro from monocytes of patients suffering from acute flairs show an increase in DP2 expression compared to patients in remission. Similar to ApoA-IV, PGD2 and the selective DP1 agonist BW245C influences polarization in monocyte-derived macrophages from healthy donors. In conclusion, these data suggest a potent anti-inflammatory role for the apolipoprotein A-IV in cells of the innate immune system, including eosinophils, monocytes and macrophages. The underlying pathway in this process may involve the nuclear receptor and clock gene NR1D1. Our clinical data suggest that DP2 receptor expression may play a role in non-classical monocytes, basophils and macrophages in rheumatoid arthritis.