title: Cysteinyl leukotriene E4activates human group 2 innate lymphoid cells and enhances the effect of prostaglandin D2and epithelial cytokines.
abstract: BACKGROUND
  Group 2 innate lymphoid cells (ILC2s) are a potential innate source of type 2 cytokines in the pathogenesis of allergic conditions. Epithelial cytokines (IL-33, IL-25, and thymic stromal lymphopoietin [TSLP]) and mast cell mediators (prostaglandin D2[PGD2]) are critical activators of ILC2s. Cysteinyl leukotrienes (cysLTs), including leukotriene (LT) C4, LTD4, and LTE4, are metabolites of arachidonic acid and mediate inflammatory responses. Their role in human ILC2s is still poorly understood.
  
  
  OBJECTIVE
  We sought to determine the role of cysLTs and their relationship with other ILC2 stimulators in the activation of human ILC2s.
  
  
  METHODS
  For ex vivo studies, fresh blood from patients with atopic dermatitis and healthy control subjects was analyzed with flow cytometry. For in vitro studies, ILC2s were isolated and cultured. The effects of cysLTs, PGD2, IL-33, IL-25, TSLP, and IL-2 alone or in combination on ILC2s were defined by using chemotaxis, apoptosis, ELISA, Luminex, quantitative RT-PCR, and flow cytometric assays. The effect of endogenous cysLTs was assessed by using human mast cell supernatants.
  
  
  RESULTS
  Human ILC2s expressed the LT receptor CysLT1, levels of which were increased in atopic subjects. CysLTs, particularly LTE4, induced migration, reduced apoptosis, and promoted cytokine production in human ILC2s in vitro. LTE4enhanced the effect of PGD2, IL-25, IL-33, and TSLP, resulting in increased production of type 2 and other proinflammatory cytokines. The effect of LTE4was inhibited by montelukast, a CysLT1antagonist. Interestingly, addition of IL-2 to LTE4and epithelial cytokines significantly amplified ILC2 activation and upregulated expression of the receptors for IL-33 and IL-25.
  
  
  CONCLUSIONS
  CysLTs, particularly LTE4, are important contributors to the triggering of human ILC2s in inflammatory responses, particularly when combined with other ILC2 activators.
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, NIHR Biomedical Research Centre, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Maryam
authors.initials: M
authors.lastname: Salimi
authors.affiliation: Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Oxford NIHR Biomedical Research Centre, Core Translational Immunology Laboratory, Oxford, United Kingdom.
authors.forename: Linda
authors.initials: L
authors.lastname: Stöger
authors.affiliation: Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Simei
authors.initials: S
authors.lastname: Go
authors.affiliation: Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Pavord
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, NIHR Biomedical Research Centre, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Ogg
authors.affiliation: Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Oxford NIHR Biomedical Research Centre, Core Translational Immunology Laboratory, Oxford, United Kingdom. Electronic address: luzheng.xue@ndm.ox.ac.uk.
authors.forename: Luzheng
authors.initials: L
authors.lastname: Xue
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000276:immunology*; D004537:Eicosanoic Acids / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology*; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D017999:Leukotriene E4 / Q000378:metabolism*; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D008407:Mast Cells / Q000276:immunology*; D015230:Prostaglandin D2 / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology
chemical_list: D016207:Cytokines; D004537:Eicosanoic Acids; D017999:Leukotriene E4; C094477:arachidic acid; D015230:Prostaglandin D2
keywords: Group 2 innate lymphoid cell; IL-2; IL-25; IL-33; atopic dermatitis; leukotriene E(4); prostaglandin D(2); thymic stromal lymphopoietin