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Cytokine-induced endogenous production of prostaglandin D2 is essential for human group 2 innate lymphoid cell activation

 
: Maric, J.; Ravindran, A.; Mazzurana, L.; Acker, A. van; Rao, A.; Kokkinou, E.; Ekoff, M.; Thomas, D.; Fauland, A.; Nilsson, G.; Wheelock, C.E.; Dahlen, S.-E.; Ferreiros, N.; Geisslinger, G.; Friberg, D.; Heinemann, A.; Konya, V.; Mjösberg, J.

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The journal of allergy and clinical immunology : JACI 143 (2019), No.6, pp.2202-2214.e5
ISSN: 0091-6749
ISSN: 1097-6825
ISSN: 1085-8725
English
Journal Article
Fraunhofer IME ()

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.

: http://publica.fraunhofer.de/documents/N-558593.html