Asthma susceptibility due to environmental programming of innate immunity in utero

由于子宫内先天免疫的环境编程而导致哮喘易感性

• 批准号: 10318567
• 负责人: Magdalena Maria Gorska
• 金额: $ 64.66万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318567
• 关键词: Address; Adoptive Transfer; Allergic Disease; Area; Asthma; Biological Markers; Birth Weight; Blood specimen; CD34 gene; Cell Differentiation process; Cells; Cessation of life; Childhood Asthma; Coculture Techniques; Cytoplasmic Granules; Data; Development; Diesel Exhaust; Eating; Enhancers; Environmental Exposure; Enzyme-Linked Immunosorbent Assay; Epithelial; Epithelial Cells; Exposure to; Fetal Growth Retardation; Fetal Tissues; Fetus; Flow Cytometry; Future; Goals; Granzyme; Growth; Growth Inhibitors; Health; Human; Immune response; Immunity; Impairment; In Vitro; Injections; Interleukin-13; Lead; Life; Link; Lymphocyte; Lymphoid Cell; Maternal Exposure; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolism; Microscopy; Modeling; Molecular; Mothers; Mus; Natural Immunity; Natural Killer Cells; Null Lymphocytes; Pathway interactions; Peptide Hydrolases; Predisposition; Preschool Child; Process; Production; Proteins; Risk; Role; STAT6 gene; Serum; Side; Starvation; Testing; Th2 Cells; Time; Tissues; Toxic Environmental Substances; Weight; airway epithelium; base; cell growth; cigarette smoke; cytokine; design; early childhood; early detection biomarkers; epidemiology study; fetal; functional outcomes; hematopoietic tissue; high risk; in utero; indexing; instrument; meetings; mouse model; novel; offspring; particle; prenatal; prevent; progenitor; programs; pup; receptor; reconstitution; repaired; response; therapeutic target; tissue repair; trait; transcription factor; transcriptome sequencing; transmission process

Project Summary/Abstract A growing number of epidemiological studies link childhood asthma with maternal environmental exposures with the strongest evidence provided for cigarette smoke and diesel exhaust. Mechanisms how maternal exposures lead to asthma in offspring are unknown. To address this, we developed a mouse model, inducing asthma susceptibility in young mice by exposing their mothers to diesel exhaust particles (DEP). We then discovered that asthma in this model was driven in part by natural killer (NK) cells. This finding was surprising because it did not fit into the traditional paradigm of NK cells serving as a body’s defense instrument designed to KILL. Our new data indicate, that instead, NK cells are part of a homeostatic response to REPAIR (NOT kill) fetal tissues that are metabolically-impaired by diesel exhaust, and that metabolic impairment is the primordial cause of asthma predisposition in our model. Metabolic impairment of DEP pups manifests itself in their reduced weight. The body’s first response to growth-limiting insults is induction of pro-survival factors. Accordingly, hematopoietic tissues of DEP fetuses and pups over-produce growth arrest-specific protein 6 (Gas6), a cytokine known to be induced under conditions of reduced metabolism and impaired growth to protect tissues from death and promote their repair. Tissue repair has long been linked to type-2 immune responses. Consistent with this, injections of Gas6 promote type-2 innate lymphoid cell (ILC2) activation and asthma in normal pups. We hypothesize that Gas6 effects are at least in part due to induction of a type-2 program in developing NK cells, and that this program endows NK cells with a capacity to orchestrate responses of type-2 lymphocytes. Gas6 is a recognized enhancer of NK cell development. It is also a known activator of STAT6, a transcriptional factor linked to type-2 differentiation. Accordingly, NK cell development is enhanced in DEP offspring and their mature NK cells produce the type-2 cytokine IL13. We further show that in DEP pups, NK cells drive production of epithelial IL25 and activation of ILC2 and Th2 cells. In addition to producing IL13, DEP NK cells have enhanced ability to degranulate. We propose that these two traits underlie the unique capacity of DEP NK cells to activate type-2 immunity. We show that the granule protease granzyme B (Gzmb) potently synergizes with IL13 to induce IL25 from airway epithelial cells. Our overarching hypothesis is that maternal exposure to DEP promotes asthma susceptibility in offspring by impairing their metabolism and growth; this provokes a repair response, part of which is induction of Gas6 that programs NK cells for enhanced secretion of IL13 and granzyme B, leading to production of IL25 and activation of ILC2 and Th2 cells. In Aim 1, we will study NK cell-driven mechanisms of prenatally-programmed asthma, focusing on NK cell mediators (Gzmb and IL13) and IL25. In Aim 2, we will study importance of Gas6 in NK cell programming and transmission of asthma susceptibility. In Aim 3, we will use human blood samples to test a hypothesis that over-activation of the Gas6 pathway in NK cells in early childhood is a predictor of future asthma.

项目总结/摘要 越来越多的流行病学研究将儿童哮喘与母亲环境暴露联系起来 最有力的证据是香烟烟雾和柴油废气。母性的机制 暴露导致后代哮喘的情况尚不清楚。为了解决这个问题，我们开发了一种小鼠模型， 通过将幼鼠暴露于柴油机尾气颗粒（DEP）中，研究幼鼠的哮喘易感性。然后我们 研究人员发现，在这个模型中，哮喘部分是由自然杀伤细胞（NK细胞）驱动的。这一发现令人惊讶 因为它不符合NK细胞作为人体防御工具的传统模式， 杀。我们的新数据表明，相反，NK细胞是对修复（而不是杀死）的稳态反应的一部分。 胎儿组织是代谢受损的柴油机废气，代谢障碍是原始的 哮喘易感性的原因。DEP幼崽的代谢障碍表现在它们的 减轻重量。身体对生长限制性损伤的第一反应是诱导促生存因子。 因此，DEP胎儿和幼崽的造血组织过度产生生长停滞特异性蛋白6 （Gas 6），一种已知在代谢降低和生长受损的条件下诱导的细胞因子， 保护组织免于死亡并促进其修复。长期以来，组织修复与2型免疫有关， 应答与此一致，Gas 6的注射促进2型先天淋巴样细胞（ILC 2）活化， 正常幼犬的哮喘我们假设Gas 6的作用至少部分是由于诱导了2型糖尿病。 计划在开发NK细胞，这一计划赋予NK细胞与协调能力， 2型淋巴细胞的反应。Gas 6是公认的NK细胞发育增强剂。它也是一个已知的 STAT 6激活因子，一种与2型分化相关的转录因子。因此，NK细胞的发育是 增强的DEP后代和它们的成熟NK细胞产生2型细胞因子IL 13。我们进一步表明，在 在DEP幼崽中，NK细胞驱动上皮IL 25的产生以及ILC 2和Th 2细胞的活化。除了 产生IL 13的DEP NK细胞具有增强的去免疫能力。我们认为，这两个特点是 DEP NK细胞激活2型免疫的独特能力。我们发现颗粒蛋白酶 B（Gzmb）与IL 13有效协同，从气道上皮细胞诱导IL 25。我们的首要假设是 母亲暴露于DEP会通过损害后代的新陈代谢， 生长;这引起修复反应，其中一部分是诱导Gas 6，其编程NK细胞， IL 13和颗粒酶B的分泌增强，导致IL 25的产生以及IL 2和Th 2的活化 细胞在目的1中，我们将研究NK细胞驱动的产前程序性哮喘的机制，重点是NK 细胞介质（Gzmb和IL 13）和IL 25。在目标2中，我们将研究Gas 6在NK细胞编程中的重要性 和哮喘易感性的传播。在目标3中，我们将使用人类血液样本来检验一个假设， 儿童早期NK细胞中Gas 6通路的过度激活是未来哮喘的预测因子。