Cysteinyl leukotriene E4 activates human ILC2s and enhances the effect of prostaglandin D2 and epithelial cytokines

Publication date: Available online 20 January 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Maryam Salimi, Linda Stöger, Wei Liu, Simei Go, Ian Pavord, Paul Klenerman, Graham Ogg, Luzheng Xue
BackgroundGroup 2 innate lymphoid cells (ILC2) are a potential innate source of type-2 cytokines in the pathogenesis of allergic conditions. Epithelial cytokines (IL-33, IL-25 and TSLP) and mast cell mediators (PGD2) are critical activators of ILC2s. Cysteinyl leukotrienes (cysLTs) including leukotriene C4 (LTC4), D4 and E4 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 controls was analyzed with flow cytometry. For in vitro studies, ILC2s were isolated and cultured. The effects of cysLTs, PGD2, IL-33, IL-25, TSLP, IL-2 alone or in combination on ILC2s were defined using chemotaxis, apoptosis, ELISA, luminex, qPCR and flow cytometric assays. The effect of endogenous cysLTs was assessed using human mast cell supernatants.ResultsHuman ILC2s expressed the leukotriene receptor, CysLT1, and this was increased in atopic individuals. CysLTs, particularly LTE4, induced migration, reduced apoptosis and promoted cytokine productions 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 pro-inflammatory cytokines. The effect of LTE4 was inhibited by montelukast, a CysLT1 antagonist. Interestingly, addition of IL-2 to LTE4 and epithelial cytokines significantly amplified the activation of ILC2s 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.

Teaser

The investigation on the role of cysLTs in human ILC2s leads to improved understanding of the mechanism of ILC2 activation. In environments where multiple activators of ILC2s occur simultaneously, these studies help to identify potential therapeutic strategies for allergic disorders.


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