Jovana Maric1, Avinash Ravindran2, Luca Mazzurana3, Aline Van Acker3, Anna Rao3, Efthymia Kokkinou3, Maria Ekoff2, Dominique Thomas4, Alexander Fauland5, Gunnar Nilsson6, Craig E Wheelock5, Sven-Erik Dahlén7, Nerea Ferreirós4, Gerd Geisslinger8, Danielle Friberg9, Akos Heinemann10, Viktoria Konya11, Jenny Mjösberg12. 1. Otto Loewi Research Center, Pharmacology Section, Medical University of Graz, and BioTechMed, Graz, Austria; Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. 2. Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institutet, and Clinical Immunology and transfusion medicine, Karolinska University Hospital, Stockholm, Sweden. 3. Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. 4. Institute of Clinical Pharmacology, Goethe-University Frankfurt, Pharmazentrum Frankfurt/ZAFES, Frankfurt, Germany. 5. Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. 6. Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institutet, and Clinical Immunology and transfusion medicine, Karolinska University Hospital, Stockholm, Sweden; Department of Medical Sciences, Uppsala University, Uppsala, Sweden. 7. Experimental Asthma and Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 8. Institute of Clinical Pharmacology, Goethe-University Frankfurt, Pharmazentrum Frankfurt/ZAFES, Frankfurt, Germany; Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project group Translational Medicine & Pharmacology TMP, Frankfurt, Germany. 9. Department of Clinical Science, Intervention and Technology, CLINTEC, Karolinska Institutet, Stockholm, Sweden; Department of Surgical Science, Uppsala University, Uppsala, Sweden. 10. Otto Loewi Research Center, Pharmacology Section, Medical University of Graz, and BioTechMed, Graz, Austria. 11. Otto Loewi Research Center, Pharmacology Section, Medical University of Graz, and BioTechMed, Graz, Austria; Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. Electronic address: viktoria.konya@medunigraz.at. 12. Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden; Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. Electronic address: jenny.mjosberg@ki.se.
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.
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.
Authors: Oyebola O Oyesola; Carolina Duque; Linda C Huang; Elisabeth M Larson; Simon P Früh; Lauren M Webb; Seth A Peng; Elia D Tait Wojno Journal: J Immunol Date: 2020-01-03 Impact factor: 5.422