Asthma susceptibility due to environmental programming of innate immunity in utero

项目摘要/摘要 越来越多的流行病学研究将儿童哮喘与母亲的环境暴露联系起来 为香烟烟雾和柴油废气提供了最有力的证据。机制如何母性 暴露于空气中会导致后代哮喘的情况尚不清楚。为了解决这个问题，我们开发了一个小鼠模型，诱导 通过将其母亲暴露于柴油废气颗粒物(DEP)，幼鼠对哮喘的易感性增加。然后我们 他们发现，这种模型中的哮喘部分是由自然杀伤(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范式 去杀人。我们的新数据表明，相反，NK细胞是修复(而不是杀死)的自我平衡反应的一部分。 因柴油废气而代谢受损的胎儿组织，而代谢受损是最基本的 在我们的模型中哮喘易感性的原因。DEP幼崽的代谢障碍表现在他们的 减轻了体重。身体对限制生长的侮辱的第一反应是诱导有利于生存的因素。 相应地，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 (Gas6)，一种已知在新陈代谢降低和生长受损的条件下诱导的细胞因子 保护组织免受死亡，并促进其修复。长期以来，组织修复一直与2型免疫有关 回应。与此一致的是，注射Gas6促进了2型固有淋巴样细胞(ILC2)的激活和 正常幼犬的哮喘。我们假设Gas6效应至少部分是由于诱导了2型 发展NK细胞的计划，这个计划赋予NK细胞协调的能力 2型淋巴细胞的反应。Gas6是公认的NK细胞发育增强剂。它也是一个已知的 STAT6激活物，一种与2型分化相关的转录因子。相应地，NK细胞的发育是 在DEP后代中增强，其成熟的NK细胞产生2型细胞因子IL13。我们进一步说明了这一点 DEP幼鼠，NK细胞驱动上皮性IL25的产生以及ILC2和Th2细胞的激活。除了……之外 产生IL13的DEP NK细胞脱颗粒能力增强。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。我们发现颗粒蛋白水解酶颗粒酶 B(Gzmb)可与IL13协同作用，诱导呼吸道上皮细胞产生IL25。我们最重要的假设 母亲接触DEP会损害后代的新陈代谢，从而增加子女对哮喘的易感性 生长；这激发了一种修复反应，其中一部分是诱导Gas6编程NK细胞 促进IL13和颗粒酶B的分泌，导致IL25的产生和ILC2和Th2的激活 细胞。在目标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 细胞介质(Gzmb和IL13)和IL25。在目标2中，我们将研究Gas6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Gas6通路的过度激活是未来哮喘的预测指标。

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.