Regulatory Tissue Polymorphonuclear Leukocytes Determinants of Ocular Immune Responses

调节组织多形核白细胞眼部免疫反应的决定因素

• 批准号: 9207455
• 负责人: KARSTEN GRONERT
• 金额: $ 38.18万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207455
• 关键词: Adaptive Immune System; Address; Adoptive Transfer; Affect; Agonist; American; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Area; Automobile Driving; Biological Assay; CD4 Positive T Lymphocytes; Cells; Cervical lymph node group; Cornea; Corneal Injury; Depressed mood; Disease; Down-Regulation; Dry Eye Syndromes; Effector Cell; Eicosanoid Receptor; Eicosanoids; Emigrations; Employee Strikes; Epithelial; Estrogens; Etiology; Eye; Eye Development; Eye diseases; FPR2 gene; Female; Goals; Gonadal Steroid Hormones; Health; Healthcare Systems; Homing; Host Defense; Human; Immigration; Immune; Immune response; Impaired wound healing; Inflammatory; Innate Immune System; LOX gene; Lacrimal gland structure; Leukocytes; Limbus Corneae; Lymphocyte; Lymphocyte Function; Magnetism; Mediating; Morbidity - disease rate; Mus; Nerve Regeneration; Ovariectomy; Pathogenesis; Pathway interactions; Phenotype; Pilot Projects; Population; Prevalence; Proteome; Proteomics; Recruitment Activity; Regulation; Reporter; Role; Sjogren' s Syndrome; Steroid Receptors; Stress; System; T cell regulation; T-Cell Activation; T-Lymphocyte; Testing; Testosterone; Tissues; White Blood Cell Count procedure; Woman; Wound Healing; aqueous; base; body system; cell type; eye dryness; genetic association; immunoregulation; lipid mediator; lipoxin A4; lymph nodes; male; neutrophil; novel; novel strategies; ocular surface; prevent; promoter; public health relevance; receptor; response; response to injury; sex; therapeutic target

 DESCRIPTION (provided by applicant): Polymophonuclear leukocytes (PMNL) have largely been ignored in the etiology or pathogenesis of ocular immune responses. PMNL presumed ocular role is host defense and they are considered secondary recruited pro-inflammatory cells that cause downstream collateral tissue damage. However, the dogma of a single primitive inflammatory PMNL cell type is rapidly evolving in other organ systems and distinct populations of PMNL are now recognized that regulate lymphocyte function. An immune-driven ocular disease, whose pathogenesis is initiated by aberrant activation of effector T cells, is aqueous tear deficient Dry Eye Disease, which is one of the most frequent ocular morbidities and has a striking female prevalence. The role of PMNL in Dry Eye Disease has not been investigated. A primary function of PMNL is formation and release of eicosanoids and receptors for these lipid mediators are expressed in lymphocytes. However, eicosanoid regulation of lymphocytes is a relatively unexplored area of immune regulation. In addition to driving host defense, PMNL are also the rate limiting cell type for generating the anti-inflammatory eicosanoid lipoxin A4 (LXA4). We recently provided the first evidence for marked sex-specific differences in corneal injury responses in both humans and mice and identified estrogen downregulation of an epithelial LXA4 circuit as a mechanism for delayed wound healing in females. In pilot studies, we discovered a novel LXA4-producing tissue-PMNL population in corneal limbus, lacrimal glands and cervical lymph nodes of healthy males and females. This tissue-PMNL, unlike inflammatory-PMNL, express a highly amplified LXA4 circuit and are dynamically and sex- specifically regulated during immune-driven Dry Eye Disease. The most striking sex-specific differences was that desiccating stress in females, unlike in males, triggered a remarkable decrease in lymph node PMNL numbers that remained depressed during Dry Eye Disease. Depressed lymph node PMNL in females correlated directly with decreased LXA4 formation and an early increase in activated CD4+ T cells and dry eye pathogenesis. Importantly, we identified dynamic expression of the LXA4 receptor, ALX, in T cells from draining lymph nodes. These ground breaking findings inspired three specific aims: I. Establish the role of LXA4- producing tissue-PMNL and LXA4 in the ocular surface and draining lymph nodes in immune-driven Dry Eye Disease. II. Elucidate the mechanism for tissue-PMNL and LXA4 receptor (ALX) mediated suppression of effector T cell activation using a novel ALX KO-GFP promoter reporter mouse line. III. Investigate the role of sex steroids in the female specific regulation of LXA4-producing PMNL and identify factors that recruit this novel PMNL population by proteomic and lipidomic approaches. The goals of the project are to investigate the role of tissue-PMNL, LXA4 and its receptors in immune-driven Dry Eye Disease and establish their sex-specific regulation as a significant factor and therapeutic target in aberrant effector T cell activation and initiation of ocular disease in females.

 描述（由申请人提供）：多形核白细胞（PMNL）在眼部免疫反应的病因学或发病机制中很大程度上被忽视。 PMNL 的假定眼部作用是宿主防御，它们被认为是二次募集的促炎细胞，可导致下游附带组织损伤。然而，单一原始炎症性 PMNL 细胞类型的教条正在其他器官系统中迅速发展，并且现在认识到调节淋巴细胞功能的不同 PMNL 群体。水性泪液缺乏性干眼病是一种免疫驱动的眼部疾病，其发病机制是由效应 T 细胞的异常激活引发的，是最常见的眼部疾病之一，女性患病率惊人。 PMNL 在干眼病中的作用尚未得到研究。 PMNL 的主要功能是类二十烷酸的形成和释放，这些脂质介质的受体在淋巴细胞中表达。然而，类二十烷酸对淋巴细胞的调节是一个相对未经探索的免疫调节领域。除了驱动宿主防御之外，PMNL 也是产生抗炎类二十烷酸脂氧素 A4 (LXA4) 的限速细胞类型。 我们最近提供了第一个证据，证明人类和小鼠的角膜损伤反应存在明显的性别特异性差异，并确定上皮 LXA4 回路的雌激素下调是女性伤口愈合延迟的机制。在初步研究中，我们在健康男性和女性的角膜缘、泪腺和颈淋巴结中发现了一种新的产生 LXA4 的组织 PMNL 群体。与炎症性 PMNL 不同，这种组织性 PMNL 表达高度扩增的 LXA4 回路，并且在免疫驱动的干眼病期间受到动态和性别特异性调节。最显着的性别差异是，与男性不同，女性的干燥压力会导致淋巴结 PMNL 数量显着减少，而这些淋巴结 PMNL 数量在干眼病期间仍然处于抑制状态。女性淋巴结 PMNL 降低与 LXA4 形成减少、活化 CD4+ T 细胞早期增加和干眼发病机制直接相关。重要的是，我们确定了引流淋巴结 T 细胞中 LXA4 受体 ALX 的动态表达。这些突破性的发现激发了三个具体目标： I. 确定 LXA4 产生组织 PMNL 和 LXA4 在眼表和引流淋巴结中在免疫驱动的干眼病中的作用。二.使用新型 ALX KO-GFP 启动子报告小鼠系阐明组织 PMNL 和 LXA4 受体 (ALX) 介导的效应 T 细胞激活抑制机制。三．研究性类固醇在女性 LXA4 产生特异性调节中的作用 PMNL 并通过蛋白质组学和脂质组学方法确定招募这种新型 PMNL 群体的因素。该项目的目标是研究组织-PMNL、LXA4及其受体在免疫驱动的干眼病中的作用，并将其性别特异性调节作为女性异常效应T细胞激活和引发眼部疾病的重要因素和治疗靶点。