Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Radnai, B.
The role of Prostaglandin D2 receptors in inflammatory bowel diseases
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp.
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Heinemann Akos
- Hoegenauer Christoph
- Schicho Rudolf
- Altmetrics:
- Abstract:
- Inflammatory bowel disease (IBD) is a chronic and recurring inflammation of the gastrointestinal tract. IBD affects approximately 5 million people in the world and meanwhile its prevalence and incidence (i.e. the number of newly identified patients) is continuously rising. IBD can be subdivided into two main forms, namely ulcerative colitis (UC) and Crohn’s disease (CD). The etiology of IBD still remains unclear, however, it has been suggested to originate from a few sensitizing factors, including genetic background, environmental triggers, colonic microbiota and from inadequate immune responses against microbes. As a fatal consequence of long persisting IBD, colitis-associated cancer can develop. Current therapy involves anti-inflammatory medication, which intends to put IBD-patients into remission. PGD2 receptors, i.e. chemoattractant receptor-homologues expressed in Th2 cells (CRTH2) and D-type prostanoid receptor-1 (DP) have been long known to be involved in many inflammatory disorders, but little is known about their role in IBD. Thus, we called into question, whether CRTH2 and DP could have an influence in the pathomechanism of UC and CD by exploring this topic in human samples, and in two experimental in vivo models of colitis, which share important features with human IBD. We detected elevated concentrations of prostanoids in sera and higher amounts of CRTH2 receptor protein in the colon of UC and CD patients, as compared to their respective control subjects. Conversely, blood eosinophils isolated from UC-patients showed attenuated levels of membrane bound CRTH2. Eosinophils isolated from control subjects showed intense internalization of CRTH2 upon receptor activation. These findings suggested a crucial role of the PGD2 - CRTH2 signaling axis in human IBD. To learn more about the role of PGD2 receptors in colitis, we tested whether in vivo pharmacological inhibition of CRTH2 (with the antagonists Cay10595 and OC-459) and of DP (with MK0524 as a DP antagonist) would have an effect. We used dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce UC-like and CD-like forms of experimental colitis, respectively, in mice. The CRTH2 antagonists Cay10595 and OC-459 improved the symptoms of colitis by inhibiting leukocyte recruitment; however, the two different inhibitors caused two different leukocyte profiles in the colon of DSS- and TNBS-colitic mice. MK0524 alone worsened the severity of colitis and in combination with OC-459, it eliminated the beneficial anti-inflammatory effects of CRTH2-antagonism. This phenomenon led us to hypothesize that an interaction between CRTH2 and DP may exist. To investigate this mechanism, we activated CRTH2 and DP with DK-PGD2 (a CRTH2 agonist) or PGD2 (CRTH2 and DP agonist) in eosinophils and tested the effects of CRTH2 and DP-antagonists (OC-459 and MK0524, respectively) by measuring migration. Our findings suggested a clear pro-migratory activity for CRTH2 in eosinophils and in contrast to this, a pro- and/or anti-migratory activity of DP that depended on the receptor’s ligand-binding state. Furthermore, we found that DP receptors modulate CRTH2 signaling, suggesting an interplay between the two receptors. In vivo, CRTH2-antagonism might have affected inhibition of eosinophil migration. Finally, we found that eosinophils played a clear pro-inflammatory role in the TNBS-model by using eosinophil-depleted ¿dbl-GATA knockout mice and IL-5 transgene mice with eosinophilia. In conclusion, based on our findings, CRTH2 antagonists (few of them are currently being tested in clinical trials as a future therapy in asthma) might be interesting as novel therapeutics for future IBD treatment.