LTB4-BLT1轴对IL-33和2型固有淋巴样细胞（ILC2）的作用及其介导过敏性气道炎症的机制研究

Type 2 immunity-mediated airway inflammation contributes largely to the pathogenesis of allergic asthma. Th2 cells are the classic type 2 immune cell that mediate allergic inflammation, while ILC2 are newly found type 2 immune cells that are the major cell source of IL-5 and IL-13 upon IL-33 stimulation during the early phase of allergic inflammation. ILC2 can mediate allergic inflammation independently of T cells, and involved in the development of Th2 immune response. LTB4 is an important inflammatory mediator, and rapidly released during early phase of inflammation. BLT1 is the major functional receptor of LTB4. Our preliminary data demonstrated that lung tissue-derived ILC2 expressed functional BLT1; and exhibited there were obvious decreases in IL-33 expression, ILC2 numbers and the expression of IL-5 and IL-13 in lung tissues of BLT1-/- mice upon challenge of protease allergen. We hypothesized that the LTB4-BLT1 axis could activate ILC2 directly or indirectly by up-regulating IL-33 expression, which could consequently contribute to the induction of Th2 immune response. In order to test our hypothesis, we are planning to take advantage of asthma model induced by allergen sensitization via airway, and interrupt the LTB4-BLT1 axis during T cell-independent and T cell-dependent allergic inflammatory stage, respectively. This project aims to determine the role of LTB4-BLT1 axis in the development of allergic asthma by orchestrating ILC2 and Th2 cells, the major two kinds of type 2 immune cells, and clarify the cellular and molecular mechanism by which LTB4-BLT1 axis regulates IL-33 expression. The work on this project may broaden our understanding of how ILC2 are activated in the tissue environment, and provide potential therapeutic target against allergic diseases.

2型免疫炎症是引起过敏性哮喘的主要原因。Th2是经典的2型免疫细胞， 而ILC2是一类新发现的2型免疫细胞，主要受IL-33活化，产生IL-5和IL-13，可介导非T细胞依赖的过敏炎症，并参与Th2应答。LTB4是一类重要炎症介质，BLT1是其主要受体。我们的前期研究发现肺组织ILC2表达功能性BLT1；过敏原刺激的BLT1-/-小鼠肺组织的IL-33表达下降、ILC2数目减少、IL-13和IL-5的表达降低。我们假设LTB4-BLT1轴直接或上调IL-33间接活化ILC2，参与诱导Th2应答。我们将利用气道致敏诱导的哮喘模型，在不依赖和依赖T细胞的炎症阶段分别阻断LTB4-BLT1轴，明确LTB4-BLT1轴在协调ILC2和Th2细胞，促进过敏性哮喘中所起的作用，阐明LTB4-BLT1轴对IL-33表达的调控机制，拓展对组织环境中ILC2活化机制的认识，为过敏性疾病的治疗提供潜在新靶点。

上皮细胞通过分泌促2型细胞因子，尤其是白细胞介素33（IL-33），调控2型固有淋巴细胞（type 2 innate lymphoid cells，ILC2），从而在对吸入性蛋白酶过敏原的变应性致敏中发挥重要作用。白三烯B4（lLTB4）是一种公认的白细胞趋化因子，通过与其1型受体（BLT1）结合发挥作用。然而，尚不明确LTB4-BLT1轴在气道过敏性致敏中的作用。为确认LTB4-BLT1轴是否或如何影响肺的IL-33表达、ILC2活化以及对经气道吸入性过敏原致敏，我们利用多种体内外模型评估了LTB4-BLT1轴对IL-33表达和ILC2活化的影响。我们也构建了嵌合体小鼠以评估非免疫细胞中BLT1的表达对过敏性致敏的影响。我们的研究发现，木瓜蛋白酶的吸入可诱导LTB4的快速释放，且早于IL-33的上调表达。在致敏期通过基因或药物干预阻断LTB4-BLT1轴可显著下调木瓜蛋白酶诱导的IL-33表达水平、ILC2活化及树突状细胞（DC）向引流淋巴结的迁徙，导致过敏性Th2反应受损。经鼻给予野生型（WT）小鼠LTB4可导致ILC2的活化，但这一现象没有出现在Il33-/-和Ltb4r1-/-小鼠中。此外，BLT1在原代小鼠ECs或正常人类支气管细胞系（NHBE）中表达，木瓜蛋白酶可以诱导NHBE分泌LTB4，进而通过BLT1激活Akt信号，促进IL-33的产生。与此一致的是在抗辐射结构细胞缺乏BLT1的嵌合体小鼠对木瓜蛋白酶产生过敏性肺部炎症程度明显降低。这样，我们的研究确定了LTB4-BLT1轴作为一个重要的上游信号，通过激活肺上皮细胞中的Akt来调节IL-33的表达，并首次揭示了LTB4-BLT1轴通过直接作用于非免疫细胞(最有可能是上皮细胞)来控制气道过敏性致敏。我们的发现也强调了上皮细胞在粘膜炎症反应启动中的作用，并拓展了我们对通过呼吸道粘膜致敏机制的理解。

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