Cysteinyl leukotriene E 4 activates human group 2 innate lymphoid cells and enhances the effect of prostaglandin D 2 and epithelial cytokines

Abstract

BackgroundGroup 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.ObjectivesWe sought to determine the role of cysLTs and their relationship with other ILC2 stimulators in the activation of human ILC2s.MethodsFor 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.ResultsHuman 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. LTE4 enhanced the effect of PGD2, IL-25, IL-33, and TSLP, resulting in increased production of type 2 and other proinflammatory cytokines. The effect of LTE4 was inhibited by montelukast, a CysLT1 antagonist. Interestingly, addition of IL-2 to LTE4 and epithelial cytokines significantly amplified ILC2 activation and upregulated expression of the receptors for IL-33 and IL-25.ConclusionCysLTs, particularly LTE4, are important contributors to the triggering of human ILC2s in inflammatory responses, particularly when combined with other ILC2 activators.

Leukotriene C4 Potentiates IL-33–Induced Group 2 Innate Lymphoid Cell Activation and Lung Inflammation

“…In the first report, LTE4 was shown to synergize with prostaglandin D2, as well as IL-25, IL-33, and TSLP to activate human ILC2s. The CysLTs also promoted ILC2 migration and survival in addition to synergistic IL-13 production (47). The second study utilized a Nippostronglyus brasiliensis parasite model to show that CysLT1R was required for ILC2 responses and type 2 inflammation.…”

Evidence for the induction of Th2 inflammation by group 2 innate lymphoid cells in response to prostaglandin D2 and cysteinyl leukotrienes in allergic rhinitis

“…Mast cells and various inflammatory cells release lipid mediators such as PGD 2 and cysLTs in early‐ and late‐phase responses in AR . Recently, it has been reported that ILC2s expressed a PGD 2 receptor, chemoattractant receptor‐homologous molecule‐expressed Th2 cells (CRTH2) and a cysLTs receptor, CysLT1, in human peripheral blood samples, and that PGD 2 and cysLTs induced the production of Th2 cytokines from ILC2s . In the present study, we hypothesized that antigen‐induced production of PGD 2 and cysLTs in the nasal mucosa stimulate tissue‐resident ILC2s to produce Th2 cytokines, initiating allergic inflammation including eosinophil infiltration in AR.…”

Type 2 Cytokine Responses: Regulating Immunity to Helminth Parasites and Allergic Inflammation

“…1), leukotrienes (LTC4, LTD4 and LTE4)(69, 70), the TNF-family cytokine TL1A(71), ICOS-ICOSL interactions(72) and the previously mentioned autocrine IL-9 pathways(49). Remarkably, three independent groups have recently highlighted a novel mechanism for ILC2 activation via the action of the neuropeptide neuromedin U (NMU)(73–75).…”