TLR4-DEPENDENT INNATE IMMUNITY IN POLLEN-TRIGGERED OCULAR ALLERGIC INFLAMMATION

描述（由申请人提供）：花粉是一种普遍存在的过敏原，影响大量过敏性疾病人群。然而，导致花粉过敏原诱导的炎症消退的机制仍然知之甚少，这一知识差距阻碍了我们开发新的靶向疗法来治愈过敏性疾病。我们最近发现了一种新的花粉/TLR 4先天免疫途径，其中短豚草（SRW）花粉通过粘膜上皮产生促过敏细胞因子胸腺基质淋巴细胞生成素（TSLP）的TLR 4依赖性先天信号传导引发过敏性炎症。因此，我们将我们的研究扩展到另一种上皮促过敏细胞因子白细胞介素（IL）33和其他可能对花粉过敏原产生反应的主要先天免疫细胞。我们推测，TLR 4依赖性先天免疫的眼粘膜上皮细胞，树突状细胞和巨噬细胞在响应花粉过敏原，启动Th 2占主导地位的过敏性炎症通过两个刺激过敏途径，TSLP/OX 40 L/OX 40和IL-33/ST 2，抑制保护性信号IL-27/IL-10。该项目的长期目标是发现治疗过敏性疾病的新分子机制和新的治疗靶点。提出了四个具体目标，以实现这一新的公共卫生项目。目的1：证实SRW花粉通过激活TLR 4/MyD 88/NF-κB天然免疫途径刺激眼上皮细胞产生TSLP和IL-33;目的2是研究树突状细胞的TLR 4依赖性先天免疫应答通过自分泌激活TSLP/OX 40 L和IL-33/IL-10来放大Th 2优势炎症的假说。SRW花粉过敏原诱导的ST 2信号转导及IL-27的抑制性调节目的3：探讨SRW花粉变应原诱导巨噬细胞向交替激活（M2）表型极化，从而促进Th 2诱导细胞因子产生的假说目的4是测试花粉/TLR 4概念可以使用TLR 4拮抗剂和/或激动剂产生用于花粉触发的过敏性疾病的新型TLR 4靶向疗法的假设。本课题的研究结果将揭示花粉过敏原通过TLR 4依赖的天然免疫应答激活黏膜天然免疫系统中的TSLP/OX 40 L/OX 40和IL-33/ST 2过敏通路，抑制IL-27/IL-10保护信号通路，从而引发Th 2型显性过敏性炎症的新现象和分子机制。该项目的最终产品将是一个基本的新认识和潜在的TLR 4靶向治疗策略，预防和治疗过敏性疾病的新希望。

DESCRIPTION (provided by applicant): Pollen is a ubiquitous allergen that affects a large population with allergic diseases. However, the mechanisms leading to resolution of pollen allergen-induced inflammation remain poorly understood, a knowledge gap preventing us from developing new targeted therapies to cure allergic diseases. We have recently uncovered a novel pollen/TLR4 innate immunity pathway where short ragweed (SRW) pollen triggers allergic inflammation via TLR4-dependent innate signaling by mucosal epithelium that produces proallergic cytokine thymic stromal lymphopoietin (TSLP). We thus extended our investigation to another epithelial proallergic cytokine interleukine (IL) 33 and other major innate immune cells that may respond to pollen allergen. We hypothesize that TLR4-dependent innate immunity by ocular mucosal epithelia, dendritic cells and macrophages in response to pollen allergen, initiates Th2-dominant allergic inflammation via two stimulated allergic pathways, TSLP/OX40L/OX40 and IL-33/ST2, with an inhibited protective signaling IL-27/IL-10. The long-term goal of this project is to discover new molecular mechanisms and novel therapeutic targets for treating allergic diseases. Four Specific Aims are proposed to fulfill this novel project for public health. Aim 1 is to confirm the hypothesis that SRW pollen stimulates production of two pro-allergic cytokines TSLP and IL-33 by ocular epithelium via activating TLR4/MyD88/NF-κB innate immunity pathway; Aim 2 is to investigate the hypothesis that TLR4-dependent innate immune responses by dendritic cells amplify Th2-dominant inflammation via autocrine activation of TSLP/OX40L and IL-33/ST2 signaling with inhibitory regulation of IL-27 in response to SRW pollen allergen; Aim 3 is to explore the hypothesis that SRW pollen allergen primes macrophage polarization toward an alternatively activated (M2) phenotype to promote Th2- inducing cytokines (TSLP, IL-33 and OX40L) and Th2-attracting chemokines (CCL17 and CCL22) via TLR4-dependent innate immunity; and Aim 4 is to test the hypothesis that pollen/TLR4 concept may create a novel TLR4-targeted therapy for pollen-triggered allergic diseases using TLR4 antagonists and/or agonists. At the conclusion of this project, we will uncover a novel phenomenon and molecular mechanism by which pollen allergen triggers Th2-dominant allergic inflammation via TLR4-dependent innate immune response that activates TSLP/OX40L/OX40 and IL-33/ST2 allergic pathways but suppresses IL-27/IL-10 protective signaling in mucosal innate immunity system. The end product of this project will be a fundamental new understanding and potential TLR4-targeted therapeutic strategies, a new hope to prevent and cure allergic disease.