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

描述(申请人提供)：花粉是一种普遍存在的过敏原，影响大量患有过敏性疾病的人群。然而，导致解决花粉过敏原引起的炎症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疗过敏性疾病。我们最近发现了一种新的花粉/TLR4先天免疫途径，其中短豚草(SRW)花粉通过黏膜上皮依赖TLR4的先天信号触发变态反应性炎症，产生促过敏细胞因子胸腺基质淋巴生成素(TSLP)。因此，我们将我们的研究扩展到另一种上皮致敏细胞因子白介素33和其他可能对花粉变应原有反应的主要先天免疫细胞。我们推测，TLR4依赖于眼粘膜上皮细胞、树突状细胞和巨噬细胞对花粉变应原的天然免疫，通过两条刺激的过敏途径TSLP/OX40L/OX40和IL-33/ST2启动以Th2为主的变态反应性炎症，并抑制保护性信号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。为实现这一新的公共卫生项目，提出了四个具体目标。目的1证实花粉通过激活TLR4/MyD88/NF-κB先天免疫途径刺激眼上皮细胞产生TSLP和IL-33两种致敏细胞因子的假说；目的2研究树突状细胞依赖TLR4的先天免疫应答通过自分泌激活TSLP/OX40L和IL-33/ST2信号，抑制IL-27对花粉变应原的反应，放大Th2型优势炎症反应；目的3探讨SRW花粉变应原通过依赖于TLR4的先天免疫刺激巨噬细胞极化成交替激活的(M2)表型以促进Th2诱导的细胞因子(TSLP、IL-33和OX40L)和Th2吸引趋化因子(CCL17和CCL22)的假说；目的4验证花粉/TLR4概念可能创造一种使用TLR4拮抗剂和/或激动剂的针对花粉引发的过敏性疾病的新的TLR4靶向治疗的假设。在本项目结束时，我们将揭示一种新的现象和分子机制，即花粉变应原通过依赖TLR4的先天免疫反应激活TSLP/OX40L/OX40和IL-33/ST2过敏通路，而抑制黏膜先天免疫系统中的IL-27/IL-10保护信号，从而触发Th2显性变态反应性炎症。该项目的最终产品将是一个根本性的新认识和潜在的TLR4靶向治疗策略，为预防和治疗过敏性疾病带来新的希望。

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.