Cytokine-induced endogenous production of prostaglandin D2 is essential for human group 2 innate lymphoid cell activation - 06/06/19
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Abstract |
Background |
Group 2 innate lymphoid cells (ILC2s) play a key role in the initiation and maintenance of type 2 immune responses. The prostaglandin (PG) D2–chemoattractant receptor–homologous molecule expressed on TH2 cells (CRTH2) receptor axis potently induces cytokine production and ILC2 migration.
Objective |
We set out to examine PG production in human ILC2s and the implications of such endogenous production on ILC2 function.
Methods |
The effects of the COX-1/2 inhibitor flurbiprofen, the hematopoietic prostaglandin D2 synthase (HPGDS) inhibitor KMN698, and the CRTH2 antagonist CAY10471 on human ILC2s were determined by assessing receptor and transcription factor expression, cytokine production, and gene expression with flow cytometry, ELISA, and quantitative RT-PCR, respectively. Concentrations of lipid mediators were measured by using liquid chromatography–tandem mass spectrometry and ELISA.
Results |
We show that ILC2s constitutively express HPGDS and upregulate COX-2 upon IL-2, IL-25, and IL-33 plus thymic stromal lymphopoietin stimulation. Consequently, PGD2 and its metabolites can be detected in ILC2 supernatants. We reveal that endogenously produced PGD2 is essential in cytokine-induced ILC2 activation because blocking of the COX-1/2 or HPGDS enzymes or the CRTH2 receptor abolishes ILC2 responses.
Conclusion |
PGD2 produced by ILC2s is, in a paracrine/autocrine manner, essential in cytokine-induced ILC2 activation. Hence we provide the detailed mechanism behind how CRTH2 antagonists represent promising therapeutic tools for allergic diseases by controlling ILC2 function.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Group 2 innate lymphoid cells, prostaglandin D2, chemoattractant receptor–homologous molecule expressed on TH2 cells, allergy
Abbreviations used : CBMC, CRTH2, DK-PGD2, DP1, 15d-PGJ2, HPGD, HPGDS, ILC2, IMDM, LC-MS/MS, LPGDS, LT, NHS, PE, PGD2, PPAR-γ, RT-qPCR, TSLP, TXB2
Plan
This project received funding from the Swedish Research Council (521-2013-2791), the Swedish Cancer Society (130396), the Foundation for Strategic Research (ICA12-0023), and the Swedish Society for Medical Research (to J. Mjösberg); the Austrian Science Fund FWF (grant P25531-B23; to V.K.); PhD Program DK-MOLIN (FWF-W1241; to J. Maric); Deutsche Forschungsgemeinschaft DFG (SFB 1039, Z01; to G.G.); the Swedish Research Council, and the Swedish Heart-Lung Foundation (to G.N.). A.F. was funded by the Karin and Sten Mörstedt Initiative on Anaphylaxis. C.E.W. was supported by the Swedish Heart-Lung Foundation (HLF 20150640 and HLF 20140469). S.-E.D. acknowledges the ChAMP (Centre for Allergy Research Highlights Asthma Markers of Phenotype) consortium, which is funded by the Swedish Foundation for Strategic Research, the Karolinska Institutet, AstraZeneca & the Science for Life Laboratory Joint Research Collaboration, and the Vårdal Foundation. |
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Disclosure of potential conflict of interest: A. Heinemann has received consultancy fees from AstraZeneca and Bayer. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 143 - N° 6
P. 2202 - juin 2019 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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