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首页> 外文期刊>Science Immunology >Tuft cell–produced cysteinyl leukotrienes and IL-25 synergistically initiate lung type 2 inflammation
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Tuft cell–produced cysteinyl leukotrienes and IL-25 synergistically initiate lung type 2 inflammation

机译：簇细胞 - 生产的白细胞生产和IL-25协同启动2型肺部炎症

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Aeroallergen sensing by airway epithelial cells triggers pathogenic immune responses leading to type 2 inflammation, the hallmark of chronic airway diseases such as asthma. Tuft cells are rare epithelial cells and the dominant source of interleukin-25(IL-25), an epithelial cytokine, and cysteinyl leukotrienes (CysLTs), lipid mediators of vascular permeability and chemotaxis. How these two mediators derived from the same cell might cooperatively promote type 2 inflammation in the airways has not beenclarified. Here, we showed that inhalation of the parent leukotriene C4 (LTC4) in combination with a subthreshold dose of IL-25 led to activation of two innate immune cells: inflammatory type 2 innate lymphoid cell (ILC2) for proliferation and cytokineproduction, and dendritic cells (DCs). This cooperative effect led to a much greater recruitment of eosinophils and CD4+ T cell expansion indicative of synergy. Whereas lung eosinophilia was dominantly mediated through the classical CysLT receptor CysLT1R, type 2 cytokines and activation of innate immune cells required signaling through CysLT1R and partially CysLT2R. Tuft cell–specific deletion of Ltc4s, the terminal enzyme required for CysLT production, reduced lung inflammation and the systemic immune response after inhalation of the mold aeroallergen Alternaria; this effect was further enhanced by concomitant blockade of IL-25. Our findings identified a potent synergy of CysLTs and IL-25 downstream of aeroallergen-trigged activation of airway tuftcells leading to a highly polarized type 2 immune response and further implicate airway tuft cells as powerful modulators of type 2 immunity in the lungs.
机译：气道上皮细胞通过气道传感触发导致2型炎症的致病免疫反应，这是慢性气道疾病（如哮喘）的标志。簇细胞是罕见的上皮细胞，是白介素25（IL-25），上皮细胞因子和白细胞三烯（CYSLTS），血管渗透性和趋化性的脂质介质的主要来源。这两个源自同一细胞的介体如何合作促进气道中的2型炎症尚未得到逆转。在这里，我们表明，与IL-25的亚阈值剂量联合吸入父白细胞C4（LTC4），导致了两个先天免疫细胞的激活：2型炎性2型先天性淋巴样细胞（ILC2），用于增殖和细胞质生产，以及树枝状细胞，以及树枝状细胞，以及树突状细胞。 （DCS）。这种合作效应导致嗜酸性粒细胞和CD4+ T细胞膨胀的募集更大，指示了协同作用。尽管肺嗜酸性粒细胞主要通过经典的CYSLT受体Cyslt1R介导，而2型细胞因子和先天免疫细胞的激活需要通过Cyslt1R和部分CYSLT2R进行信号传导。 LTC4S的TUFT细胞特异性缺失，CYSLT产生所需的末端酶，减少肺部炎症和吸入模具灭气酸酯替代品后的全身免疫反应; IL-25的伴随封锁进一步增强了这种效果。我们的发现确定了cyslts和IL-25的有效协同作用，使气道簇的气道簇激活，导致高度极化的2型免疫反应，并进一步将气道簇细胞作为肺部2型免疫力的强大调节剂。

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