Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Frei-Winterleitner, R.
Cannabinoid receptor 2 activation as a novel priming
factor for human and mouse eosinophils
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2016. pp.
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Heinemann Akos
- Sattler Wolfgang
- Altmetrics:
- Abstract:
- Background and Methods: Allergic inflammation is characterized by an accumulation of activated eosinophils in the affected tissue. Recently, the endocannabinoid system, via activation of CB2 by the endogenous ligand 2-arachidonoylglycerol was shown to induce migration of human eosinophils. However, further reports identified several other mechanisms like cytokine priming and metabolism of 2-AG into eicosanoids that might contribute to this effect. Thus, in this study I focused on the contribution of selective CB2 activation by the agonist JWH-133 on human and mouse eosinophil function in vitro and in vivo. Eosinophil responsiveness was studied in assays of adhesion, migration, respiratory burst, degranulation and Ca2+ release. Furthermore, potentially altered CB2 expression under allergic condition was analyzed. The contribution of the endocannabinoid system to allergic airway inflammation was assessed in established mouse models. Results and Conclusion: CB2 expression was significantly enhanced in eosinophils of allergic donors with respiratory symptoms, compared to healthy control. Selective activation of CB2 only induced a moderate migratory response in human eosinophils but greatly enhanced the effects of chemoattractants on shape change, migration, expression of surface integrins, adhesion and reactive oxygen species production. Using the selective cannabinoid receptor 2 antagonist SR144528 I could confirm that these effects are indeed mediated by CB2 activation rather than eicosanoid metabolism. Systemic application of JWH-133 in a setting of directed eosinophil migration and ovalbumininduced allergic asthma in mice clearly elevated eosinophil influx into the airways and airway hyperresponsiveness in a CB2 dependent manner. Interestingly the latter effect was completely absent in eosinophil-deficient ¿dblGATA mice. To summarize, the data obtained clearly demonstrates that activation of CB2 on eosinophils represents a novel priming mechanisms and may therefore contribute to the pathogenesis of eosinophil driven diseases. Furthermore, it provides new details on the molecular machinery associated with CB2 induced priming. Concluding, antagonism of CB2 might represent an interesting molecular target for the treatment of allergic inflammation.