Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Maric, J.
Role of prostaglandins in regulation of human group 2 innate lymphoid cell function
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp. 113
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Heinemann Akos
- Konya Viktoria
- Altmetrics:
- Abstract:
- Innate lymphoid cells (ILCs) are a recently identified family of lymphoid cells lacking expression of lineage markers and antigen receptors. Group 2 innate lymphoid cells (ILC2) are involved in the initiation and amplification of type 2 immune responses. Upon allergen or pathogen stimulation, the airway epithelium-derived innate cytokines IL-33, IL-25 and thymic stromal lymphopoietin (TSLP) activate ILC2. These events lead to production of type 2 cytokines IL-5 and IL-13 by ILC2, which contribute to asthma and allergic inflammation. Lipid mediators have been shown to play important roles in ILC2 biology. Prostaglandin E2 (PGE2), a bioactive lipid abundantly present in the lung, mediates protective effects in allergic responses. Thus, in the first part of my thesis, the aim was to reveal the role of PGE2 in regulating human ILC2 function. I demonstrated that PGE2 inhibits production and release of IL-5 and IL-13 from human tonsil and blood ILC2 in response to stimulation with activating cytokines IL-33, IL-25, TSLP plus IL-2. PGE2 affects molecular pathways important for ILC2 activation, as it reduces upregulation of GATA3 and CD25 expression and blocks ILC2 proliferation. Additionally, I showed that the suppressive effects of PGE2 are mediated through simultaneous engagement of EP2 and EP4 receptors, PGE2 receptors which are specifically expressed on ILC2. Another lipid mediator, PGD2, has been shown to induce cytokine production and migration of ILC2 via CRTH2 receptor activation. In the second part of the thesis, my objective was to determine whether ILC2 are capable of prostaglandin, in particular PGD2 production, on their own and what would be the impact of such a process in ILC2 function. I showed that ILC2 constitutively express hematopoietic PGD2 synthesis (HPGDS) and highly upregulate COX-2 upon stimulation with activating cytokines. Consequently, PGD2 pathway is induced, as PGD2 and its metabolites are detected in the supernatants of stimulated ILC2. Importantly, I revealed that, upon cytokine stimulation, endogenously produced PGD2, acting in an autocrine manner via CRTH2 receptor, is crucial for ILC2 responses. I proved this by demonstrating that blocking of COX-1/2 enzyme or the CRTH2 receptor inhibited cytokine-induced ILC2 activation. Overall, these data elucidate new mechanisms of ILC2 regulation on the one hand by showing the inhibitory PGE2-EP2/EP4 axis and on the other hand by revealing the stimulatory function of the endogenous PGD2-CRTH2 axis. These novel findings provide potential therapeutic approaches by targeting ILC2 function in the treatment of allergic inflammatory diseases.