Role of Microbiome Sodium Butyrate in regulation of ILC2 dependent airway hyperreactivity

项目总结 第二组先天淋巴样细胞(ILC2s)构成了最近发现的产生2型的细胞群 IL-5和IL-13等细胞因子对越来越多的环境信号和上皮细胞的响应 细胞衍生的细胞因子。最初被描述为抗蠕虫天然免疫中IL-13的关键来源， 现在的研究表明，在哮喘和许多广泛传播的过敏性疾病中，ILC2活性增加。在小鼠体内 哮喘模型、ILC2足以引起伴随呼吸道的嗜酸性炎症 不依赖适应性免疫的高反应性(AHR)。根据这些发现，确定特工 能够调节ILC2功能是推进哮喘治疗的重要一步。这 该项目的动机是我们最近发现丁酸钠，一种天然的短链脂肪酸(SCFA) 存在于我们身体的组织和体液中，通过以下方式显著抑制2型细胞因子的产生 ILC2并缓解ILC2依赖的AHR。此外，我们还发现肺内ILC2高度表达a 丁酸钠受体Gpr109a，不表达Gpr41或GPR43。进一步转录组 分析表明，在ILC2的发育和功能中关键的转录因子GATA-3是 丁酸钠治疗后显著下调。鉴于肠道细菌是 丁酸在哺乳动物中的主要来源，我们现在建议描述其机制 微生物来源的丁酸钠可能调节远端组织中ILC2效应器的功能 降低ILC2依赖的AHR。 这个研究项目的总体目标是发现一套全面的分子签名和 可用作治疗过敏性疾病和哮喘的治疗靶点的标志物。为了实现 为了达到这个目的，我们首先将全面描述钠的表型、功能和作用机制 丁酸盐在AHR动物模型中的应用。接下来，利用最近描述的ILC2人源化小鼠(Maazi等人， 免疫力2015年，Galle等人，《自然通讯》2016年)，我们打算评估 Gpr109a受体缺失时的治疗干预。最后，我们将致力于防止 通过改变高产丁酸小鼠的微生物群发展ILC2依赖的AHR 细菌菌株，并将结果与接受没有生产能力的微生物组进行比较 丁酸盐。这项翻译研究提案将提供关键线索，使我们能够开发 治疗过敏性疾病和哮喘患者的治疗方法。

PROJECT SUMMARY Group 2 innate lymphoid cells (ILC2s) constitute a recently identified cell population that produces type 2 cytokines such as IL-5 and IL-13 in response to a growing number of environmental signals and epithelial cell-derived cytokines. Initially described as a key source of IL-13 in anti-helminth innate immunity, studies now show increased ILC2 activity in asthma and many widespread allergic diseases. In murine models of asthma, ILC2s are sufficient to provoke eosinophilic inflammation accompanied by airway hyperreactivity (AHR) independent of adaptive immunity. Based on these findings, identifying agents capable of modulating ILC2 function is an important step towards advancing treatment of asthma. This project is motivated by our recent finding that sodium butyrate, a short-chain fatty acid (SCFA) naturally present in our body’s tissues and fluids, significantly suppresses the production of type 2 cytokines by ILC2s and relieves ILC2-dependent AHR. We additionally found that pulmonary ILC2s highly express a receptor for sodium butyrate, GPR109a and do not express GPR41 or GPR43. Further transcriptome analyses revealed that GATA-3, a key transcription factor in ILC2 development and function, was significantly down-regulated after treatment with sodium butyrate. Given that intestinal bacteria are the predominant source of butyrate in mammals, we now propose to characterize the mechanisms by which microbial-derived sodium butyrate potentially modulates ILC2 effector function in distal tissues and reduces ILC2-dependent AHR. The overall goal of this research project is to discover a comprehensive set of molecular signatures and markers that can be used as therapeutic targets to treat allergic disease and asthma. In order to achieve this objective, we will first fully characterize the phenotype, function, and mechanisms of action of sodium butyrate in animal models of AHR. Next, utilizing a recently described ILC2 humanized mice (Maazi et al, Immunity 2015, Galle et al, Nature Communications 2016), we intend to assess the capacity for therapeutic intervention in the presence of absence of GPR109a receptor. Finally, we will aim to prevent development of ILC2 dependent AHR via altering microbiome of mice with high butyrate producing strains of bacteria and compare the results to the recipients of microbiome without capacity to produce butyrate. This translational research proposal will provide critical clues that enable us to develop therapeutic approaches for the treatment of patients with allergic disease and asthma.