Cytokine-induced endogenous production of prostaglandin D₂ is essential for human group 2 innate lymphoid cell activation - 06/06/19

Doi : 10.1016/j.jaci.2018.10.069

Jovana Maric, PhD ^a,^b, Avinash Ravindran, MSc ^c, Luca Mazzurana, MSc ^b, Aline Van Acker, PhD ^b, Anna Rao, PhD ^b, Efthymia Kokkinou, MSc ^b, Maria Ekoff, PhD ^c, Dominique Thomas, PhD ^d, Alexander Fauland, PhD ^e, Gunnar Nilsson, PhD ^c,^f, Craig E. Wheelock, PhD ^e, Sven-Erik Dahlén, MD, PhD ^g, Nerea Ferreirós, PhD ^d, Gerd Geisslinger, MD, PhD ^d,^h, Danielle Friberg, MD, PhD ^i,^j, Akos Heinemann, MD ^a, Viktoria Konya, PhD ^a,^b,^⁎^{∗
These authors contributed equally to this work.} , Jenny Mjösberg, PhD ^b,^k,^⁎^{∗
These authors contributed equally to this work.}
^a Otto Loewi Research Center, Pharmacology Section, Medical University of Graz, and BioTechMed, Graz, Austria
^b Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
^e Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
^g Experimental Asthma and Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
ⁱ Department of Clinical Science, Intervention and Technology, CLINTEC, Karolinska Institutet, Stockholm, Sweden
^c Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institutet, and Clinical Immunology and transfusion medicine, Karolinska University Hospital, Stockholm, Sweden
^d Institute of Clinical Pharmacology, Goethe-University Frankfurt, Pharmazentrum Frankfurt/ZAFES, Frankfurt, Germany
^f Department of Medical Sciences, Uppsala University, Uppsala, Sweden
^h Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project group Translational Medicine & Pharmacology TMP, Frankfurt, Germany
^j Department of Surgical Science, Uppsala University, Uppsala, Sweden
^k Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden

^∗Corresponding author: Jenny Mjösberg, PhD, Center for Infectious Medicine, F59, Karolinska Institutet, S-14186 Stockholm, Sweden.Center for Infectious MedicineF59, Karolinska InstitutetStockholmS-14186Sweden^∗Viktoria Konya, PhD, Otto Loewi Research Center, Pharmacology Section, Medical University of Graz, Graz, Austria.Otto Loewi Research CenterPharmacology SectionMedical University of GrazGrazAustria

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 T_H2 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

Le texte complet de cet article est disponible en PDF.

Key words : Group 2 innate lymphoid cells, prostaglandin D₂, chemoattractant receptor–homologous molecule expressed on T_H2 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

Methods

Isolation and flow cytometric sorting of tonsillar and blood ILC2s

Culture, expansion, and treatments of ILC2s

Flow cytometric staining and analysis of intracellular cytokines

Mast cell culture and stimulation

ELISA

Liquid chromatography–tandem mass spectrometry

Quantitative RT-PCR

Statistical analyses

Results

Production of IL-5 and IL-13 by ILC2s is dependent on endogenous PGs

The PGD₂ pathway is turned on in stimulated human ILC2s

Activation of ILC2s on cytokine stimulation depends on endogenous PGD₂

Endogenously produced PGD₂ is crucial for cytokine-induced activation of freshly isolated blood and tonsillar ILC2s

Discussion

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.

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.

Export

Vol 143 - N° 6

P. 2202 - juin 2019 Retour au numéro

Article précédent

Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid
Hideaki Morita, Terufumi Kubo, Beate Rückert, Avinash Ravindran, Michael B. Soyka, Arturo Ottavio Rinaldi, Kazunari Sugita, Marcin Wawrzyniak, Paulina Wawrzyniak, Kenichiro Motomura, Masato Tamari, Keisuke Orimo, Naoko Okada, Ken Arae, Kyoko Saito, Can Altunbulakli, Francesc Castro-Giner, Ge Tan, Avidan Neumann, Katsuko Sudo, Liam O'Mahony, Kenya Honda, Susumu Nakae, Hirohisa Saito, Jenny Mjösberg, Gunnar Nilsson, Kenji Matsumoto, Mübeccel Akdis, Cezmi A. Akdis

| Article suivant

IFN-? and CD25 drive distinct pathologic features during hemophagocytic lymphohistiocytosis
Stéphanie Humblet-Baron, Dean Franckaert, James Dooley, Fatima Ailal, Aziz Bousfiha, Caroline Deswarte, Carmen Oleaga-Quintas, Jean-Laurent Casanova, Jacinta Bustamante, Adrian Liston

Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.

Déjà abonné à cette revue ?

connectez-vous ou créez un compte

Cytokine-induced endogenous production of prostaglandin D₂ is essential for human group 2 innate lymphoid cell activation - 06/06/19

Abstract

Background

Objective

Methods

Results

Conclusion

Graphical abstract

Plan

Export citations

Fichier

Contenu

Accès rapides

Mon compte

Aide & support

Plateformes Elsevier Masson

Déclaration CNIL