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Cytokine-Induced Endogenous Production of Prostaglandin D2 Is Essential for Human Group 2 Innate Lymphoid Cell Activation

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Cytokine-Induced Endogenous Production of Prostaglandin D2 Is Essential for Human Group 2 Innate Lymphoid Cell Activation Cytokine-induced endogenous production of prostaglandin D2 is essential for human group 2 innate lymphoid cell activation 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 Dahlen, MD, PhD,g Nerea Ferreiros, PhD,d Gerd Geisslinger, MD, PhD,d,h Danielle Friberg, MD, PhD,i,j Akos Heinemann, MD,a Viktoria Konya, PhD,a,b* and Jenny Mjosberg,€ PhDb,k* Graz, Austria; Stockholm, Uppsala, and Linkoping,€ Sweden; and Frankfurt, Germany GRAPHICAL ABSTRACT Background: Group 2 innate lymphoid cells (ILC2s) play a key receptor–homologous molecule expressed on TH2 cells (CRTH2) role in the initiation and maintenance of type 2 immune receptor axis potently induces cytokine production and ILC2 responses. The prostaglandin (PG) D2–chemoattractant migration. From athe Otto Loewi Research Center, Pharmacology Section, Medical University of G.G.); the Swedish Research Council, and the Swedish Heart-Lung Foundation (to € Graz, and BioTechMed, Graz; bthe Center for Infectious Medicine, Department of G.N.). A.F. was funded by the Karin and Sten Morstedt Initiative on Anaphylaxis. Medicine Huddinge, ethe Division of Physiological Chemistry II, Department of Med- C.E.W. was supported by the Swedish Heart-Lung Foundation (HLF 20150640 and ical Biochemistry and Biophysics, gExperimental Asthma and Allergy Research, Insti- HLF 20140469). S.-E.D. acknowledges the ChAMP (Centre for Allergy Research tute of Environmental Medicine, and ithe Department of Clinical Science, Intervention Highlights Asthma Markers of Phenotype) consortium, which is funded by the Swed- and Technology, CLINTEC, Karolinska Institutet, Stockholm; cthe Immunology and ish Foundation for Strategic Research, the Karolinska Institutet, AstraZeneca & the Allergy Unit, Department of Medicine, Solna, Karolinska Institutet, and Clinical Science for Life Laboratory Joint Research Collaboration, and the Vardal Foundation. Immunology and transfusion medicine, Karolinska University Hospital, Stockholm; Disclosure of potential conflict of interest: A. Heinemann has received consultancy fees dthe Institute of Clinical Pharmacology, Goethe-University Frankfurt, Pharmazentrum from AstraZeneca and Bayer. The rest of the authors declare that they have no relevant Frankfurt/ZAFES, Frankfurt; fthe Department of Medical Sciences, Uppsala Univer- conflicts of interest. sity; hthe Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Proj- Received for publication September 20, 2017; revised August 8, 2018; accepted for pub- ect group Translational Medicine & Pharmacology TMP, Frankfurt; jthe Department lication October 11, 2018. € of Surgical Science, Uppsala University; and kthe Department of Clinical and Exper- Corresponding author: Jenny Mjosberg, PhD, Center for Infectious Medicine, F59, Kar- imental Medicine, Linkoping€ University. olinska Institutet, S-14186 Stockholm, Sweden. E-mail: [email protected]. Or: *These authors contributed equally to this work. Viktoria Konya, PhD, Otto Loewi Research Center, Pharmacology Section, Medical This project received funding from the Swedish Research Council (521-2013-2791), the University of Graz, Graz, Austria. E-mail: [email protected]. Swedish Cancer Society (130396), the Foundation for Strategic Research (ICA12- 0091-6749/$36.00 Ó 0023), and the Swedish Society for Medical Research (to J. Mjosberg);€ the Austrian 2018 American Academy of Allergy, Asthma & Immunology Science Fund FWF (grant P25531-B23; to V.K.); PhD Program DK-MOLIN (FWF- https://doi.org/10.1016/j.jaci.2018.10.069 W1241; to J. Maric); Deutsche Forschungsgemeinschaft DFG (SFB 1039, Z01; to 1 2 MARIC ET AL J ALLERGY CLIN IMMUNOL nnn 2019 Objective: We set out to examine PG production in human ILC2s and the implications of such endogenous production on Abbreviations used ILC2 function. CBMC: Cord blood–derived mast cell Methods: The effects of the COX-1/2 inhibitor flurbiprofen, the CRTH2: Chemoattractant receptor–homologous molecule ex- hematopoietic prostaglandin D synthase (HPGDS) inhibitor pressed on TH2 cells 2 DK-PGD : 13, 14-Dihydro-15-keto prostaglandin D KMN698, and the CRTH2 antagonist CAY10471 on human 2 2 DP1: Prostaglandin D receptor 1 ILC2s were determined by assessing receptor and transcription 2 15d-PGJ2: 15-Deoxy-delta-12, 14-PGJ2 factor expression, cytokine production, and gene expression HPGD: 15-Hydroxyprostaglandin dehydrogenase with flow cytometry, ELISA, and quantitative RT-PCR, HPGDS: Hematopoietic prostaglandin D2 synthase respectively. Concentrations of lipid mediators were measured ILC2: Group 2 innate lymphoid cell by using liquid chromatography–tandem mass spectrometry IMDM: Iscove modified Dulbecco medium and ELISA. LC-MS/MS: Liquid chromatography–tandem mass spectrometry Results: We show that ILC2s constitutively express HPGDS and LPGDS: Lipocalin prostaglandin D2 synthase upregulate COX-2 upon IL-2, IL-25, and IL-33 plus thymic LT: Leukotriene NHS: Normal human serum stromal lymphopoietin stimulation. Consequently, PGD and its 2 PE: Phycoerythrin metabolites can be detected in ILC2 supernatants. We reveal PGD2: Prostaglandin that endogenously produced PGD2 is essential in cytokine- PPAR-g: Peroxisome proliferator–activated receptor g induced ILC2 activation because blocking of the COX-1/2 or RT-qPCR: Quantitative RT-PCR HPGDS enzymes or the CRTH2 receptor abolishes ILC2 TSLP: Thymic stromal lymphopoietin responses. TXB2: Thromboxane B2 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 synthase (HPGDS), which is expressed on immune cells,14-16 for allergic diseases by controlling ILC2 function. (J Allergy and lipocalin prostaglandin D2 synthase (LPGDS), which is Clin Immunol 2019;nnn:nnn-nnn.) foundmainlyinnervoussystem,heart,andadiposetis- 17,18 19 sue. Mast cells are the major source of PGD2, whereas Key words: Group 2 innate lymphoid cells, prostaglandin D2, che- 20 21 dendritic cells, macrophages, eosinophils, and TH2 cells moattractant receptor–homologous molecule expressed on TH2 cells, release smaller amounts of PGD .22 In the metabolism of allergy 2 PGD2, 15-hydroxyprostaglandin dehydrogenase (HPGD) con- verts PGD2 into 13, 14-dihydro-15-keto prostaglandin D2 23,24 (DK-PGD2), a natural selective agonist of CRTH2 recep- tor.25 Furthermore, PGD can be nonenzymatically converted Group 2 innate lymphoid cells (ILC2s) play important roles in 2 1 into PGJ2 and its derivatives, metabolites with biological the initiation and amplification of type 2 immune responses. Un- activity.26 der inflammatory conditions, ILC2s are stimulated by the innate Because CRTH2 is a key receptor in allergic inflammatory cytokines IL-33, IL-25, and thymic stromal lymphopoietin processes and mediates the PGD2-induced activation of (TSLP), which are products of activated epithelial cells and mac- ILC2s and other type 2 immune cells, the PGD -CRTH2 rophages.2 Optimal activation of human ILC2s requires a combi- 2 3,4 axis is an emerging therapeutic target to control allergic dis- nation of these 3 cytokines, as well as IL-2. eases.22,27,28 The role of exogenous PGD in ILC2 function Furthermore, ILC2s can be activated by proinflammatory lipid 2 5 6,7 has been clearly established; however, it has not been ad- mediators. Leukotriene (LT) D4,LTE4, and prostaglandin 8-10 dressed whether endogenously produced PGD2 plays a role (PG) D2 are potent stimulators of mouse and human ILC2s. in ILC2 activation. PGD2 has been shown to induce IL-5 and IL-13 production, as 8,10,11 Our study shows that human ILC2s express HPGDS and that well as migration of ILC2s. Human ILC2s were initially IL-2, IL-25, and IL-33 plus TSLP activation of human ILC2s identified based on the expression of one of the receptors for 12 leads to upregulation of the rate-limiting COX-2 enzyme. This PGD2. The PGD2 receptor chemoattractant receptor– renders ILC2s capable of producing PGD2 and its metabolites. homologous molecule expressed on TH2 cells (CRTH2) now Endogenously produced PGD2 is essential in cytokine-induced serves as an important cell-surface marker of human ILC2s. activation of human ILC2s because a COX-1/2 blocker potently CRTH2 is a Gi protein–coupled receptor, and in type 2 immune prevents IL-5 and IL-13 production from the cells. Similarly, se- cells, such as TH2 cells, eosinophils, basophils, and ILC2s, 13 lective antagonism of CRTH2 on cytokine stimulation inhibits CRTH2 activation increases free intracellular calcium levels. ILC2 activation. Thus we demonstrate that human ILC2s criti- Activation of these cells is crucial in the development of allergic cally depend on endogenously produced PGD2 for activation by inflammatory processes. cytokines. Our results have implications for the treatment of PGD2, belonging to the eicosanoid family, is derived from allergic inflammation. arachidonic acid, which is liberated from membrane phospho- lipids by phospholipase A2. Activation of COX-1, COX-2, or both leads to a 2-step metabolism of arachidonic acid into METHODS PGG2 and subsequently to PGH2, which is the substrate for A detailed description of the methods and materials used in this study is enzymes specialized in generating different PGs. There are provided in the Methods section in this article’s Online Repository
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