Cytokine-induced endogenous production of PGD2 is essential for human ILC2 activation

Publication date: Available online 19 December 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Jovana Maric, Avinash Ravindran, Luca Mazzurana, Aline Van Acker, Anna Rao, Efthymia Kokkinou, Maria Ekoff, Dominique Thomas, Alexander Fauland, Gunnar Nilsson, Craig E. Wheelock, Sven-Erik Dahlén, Nerea Ferreirós, Gerd Geisslinger, Danielle Friberg, Akos Heinemann, Viktoria Konya, Jenny Mjösberg

Abstract

Background

Group 2 innate lymphoid cells (ILC2) play a key role in the initiation and maintenance of type 2 immune responses. The PGD₂-CRTH2 receptor axis potently induces cytokine production and migration of ILC2.

Objective

We set out to examine prostaglandin production in human ILC2 and the implications of such endogenous production on ILC2 function.

Methods

The effects of the COX-1/2 inhibitor flurbiprofen, the HPGDS inhibitor KMN698, and the CRTH2 antagonist CAY10471 on human ILC2 were determined by assessing receptor and transcription factor expression, cytokine production and gene expression by flow cytometry, ELISA and quantitative RT-PCR, respectively. Concentrations of lipid mediators were measured by LC-MS/MS and by ELISA.

Results

We show that ILC2 constitutively express hematopoietic prostaglandin D₂ synthase (HPGDS), and upregulate COX-2 upon IL-2, IL-25, IL-33 plus TSLP- 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, as blocking of the COX-1/2 or HPGDS enzymes or the CRTH2 receptor abolishes ILC2 responses.

Conclusion

PGD₂ produced by ILC2 is, in an para-/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.

Graphical abstract

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