Salimi Maryam, Stöger Linda, Liu Wei, Go Simei, Pavord Ian, Klenerman Paul, Ogg Graham, Xue Luzheng
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, NIHR Biomedical Research Centre, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
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.
J Allergy Clin Immunol. 2017 Oct;140(4):1090-1100.e11. doi: 10.1016/j.jaci.2016.12.958. Epub 2017 Jan 20.
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 D [PGD]) are critical activators of ILC2s. Cysteinyl leukotrienes (cysLTs), including leukotriene (LT) C, LTD, and LTE, are metabolites of arachidonic acid and mediate inflammatory responses. Their role in human ILC2s is still poorly understood.
We sought to determine the role of cysLTs and their relationship with other ILC2 stimulators in the activation of human ILC2s.
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, PGD, 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.
Human ILC2s expressed the LT receptor CysLT, levels of which were increased in atopic subjects. CysLTs, particularly LTE, induced migration, reduced apoptosis, and promoted cytokine production in human ILC2s in vitro. LTE enhanced the effect of PGD, IL-25, IL-33, and TSLP, resulting in increased production of type 2 and other proinflammatory cytokines. The effect of LTE was inhibited by montelukast, a CysLT antagonist. Interestingly, addition of IL-2 to LTE and epithelial cytokines significantly amplified ILC2 activation and upregulated expression of the receptors for IL-33 and IL-25.
CysLTs, particularly LTE, are important contributors to the triggering of human ILC2s in inflammatory responses, particularly when combined with other ILC2 activators.
2型固有淋巴细胞（ILC2s）是过敏性疾病发病机制中2型细胞因子潜在的固有来源。上皮细胞因子（IL-33、IL-25和胸腺基质淋巴细胞生成素[TSLP]）以及肥大细胞介质（前列腺素D[PGD]）是ILC2s的关键激活剂。半胱氨酰白三烯（cysLTs），包括白三烯（LT）C、LTD和LTE，是花生四烯酸的代谢产物，介导炎症反应。它们在人类ILC2s中的作用仍知之甚少。
我们试图确定cysLTs在人类ILC2s激活中的作用及其与其他ILC2刺激物的关系。
对于体外研究，采用流式细胞术分析特应性皮炎患者和健康对照者的新鲜血液。对于体内研究，分离并培养ILC2s。通过趋化性、凋亡、酶联免疫吸附测定（ELISA）、Luminex、定量逆转录聚合酶链反应（RT-PCR）和流式细胞术分析单独或联合使用cysLTs、PGD、IL-33、IL-25、TSLP和IL-2对ILC2s的影响。使用人肥大细胞上清液评估内源性cysLTs的作用。
人类ILC2s表达LT受体CysLT，特应性个体中其水平升高。cysLTs，尤其是LTE，在体外可诱导人类ILC2s迁移、减少凋亡并促进细胞因子产生。LTE增强了PGD、IL-25、IL-33和TSLP的作用，导致2型及其他促炎细胞因子产生增加。LTE的作用被半胱氨酰白三烯拮抗剂孟鲁司特抑制。有趣的是，将IL-2添加到LTE和上皮细胞因子中可显著增强ILC2激活并上调IL-33和IL-25受体的表达。
cysLTs，尤其是LTE，是炎症反应中触发人类ILC2s的重要因素，特别是与其他ILC2激活剂联合使用时。
