Immuno-metabolic regulation of lung inflammation

项目摘要 仅在美国，哮喘就影响了大约3900万人，并造成3,000多人死亡 每年。目前的治疗策略在患者亚组中可能无效，可能导致不良副作用， 治疗疾病的症状而不是原因。更好地理解机制 为了指导新的、更有选择性的治疗方法的发展， 治疗策略最近的研究表明，免疫细胞的重要性称为组2 先天性淋巴样细胞（ILC 2）在驱动肺部炎症如哮喘中的作用;然而， 控制这种促炎功能还没有很好地理解。特别是，尽管在 细胞代谢与多种肺部疾病的严重程度相关，无论是特定的代谢 因子影响ILC 2代谢程序并调节ILC 2功能以驱动炎性疾病 从未被检查过。这项建议的中心焦点是了解细胞内在代谢是如何进行的。 因子控制ILC 2功能以调节肺部炎症的发展。在新的初步研究中，我发现 ILC 2是精氨酸酶1（Arg 1）的主要来源，ILC 2- 内源性Arg 1抑制ILC 2反应并防止肺部炎症。此外，需要Arg 1用于 ILC 2多胺的产生和葡萄糖代谢，表明Arg 1广泛地改变了生物能量代谢。 这些代谢变化可能是ILC 2驱动肺循环的能力的基础。 炎症尽管取得了这些进展，但在上游监管信号方面仍存在根本性差距 ILC 2表达所需的Arg 1和Arg 1影响ILC 2表达的下游代谢机制 ILC 2生物能量编程和效应器功能驱动肺部炎症。使用尖端技术 在代谢谱和免疫生物学中，在这个提议中，我将剖析ILC 2-Arg 1依赖的机制， 通过研究（1）Arg 1的转录控制如何影响ILC 2来调节肺组织炎症 代谢功能和（2）Arg 1衍生的多胺如何调节ILC 2生物能量学以控制肺 炎症更深入地了解ILC 2驱动肺部炎症的信号和机制 可能导致改进的选择性治疗阻断其功能以改善肺部疾病。

PROJECT SUMMARY In the US alone, asthma affects approximately 39 million individuals and is responsible for over 3,000 deaths annually. Current therapeutic strategies can be ineffective in subgroups of patients, can cause undesired side effects, and treat the symptoms of disease rather than the cause. Greater understanding of the mechanisms that regulate inflammation in the lung is needed in order to direct the development of novel, more selective therapeutic strategies. Recent studies have demonstrated the importance of immune cells called Group 2 innate lymphoid cells (ILC2s) in driving lung inflammation such as asthma; however, the mechanisms controlling this pro-inflammatory function are not well understood. In particular, although dysregulation in cellular metabolism has been associated with severity of multiple lung diseases, whether specific metabolic factors influence ILC2 metabolic programming and modulate ILC2 functionality to drive inflammatory disease has never been examined. The central focus of this proposal is to understand how cell-intrinsic metabolic factors control ILC2 function to regulate development of lung inflammation. In new preliminary studies, I found that ILC2s were the dominant source of the amino acid enzyme Arginase 1 (Arg1), and that deletion of ILC2- intrinsic Arg1 dampened ILC2 responses and prevented lung inflammation. Furthermore, Arg1 was required for ILC2 polyamine generation and glucose metabolism, suggesting that Arg1 broadly alters the bioenergetic programming of ILC2s and that these metabolic changes may underlie the ability of ILC2s to drive lung inflammation. Despite these advances, fundamental gaps remain regarding the upstream regulatory signals required for ILC2 expression of Arg1 and the downstream metabolic mechanisms by which Arg1 influences ILC2 bioenergetic programming and effector function to drive lung inflammation. Using cutting-edge techniques in metabolic profiling and immunobiology, in this proposal I will dissect the ILC2-Arg1-dependent mechanisms regulating lung tissue inflammation by investigating (1) How transcriptional control of Arg1 affects ILC2 metabolic function and (2) how Arg1-derived polyamines regulate ILC2 bioenergetics to control lung inflammation. Greater understanding of the signals and mechanisms by which ILC2s drive lung inflammation may lead to improved, selective therapies blocking their function to ameliorate lung disease.