Nuclear receptors as metabolic relays of ILC2-mediated immune responses

先天性淋巴样细胞（ILC）的主要任务是保护和维持组织屏障。然而，ILC的慢性激活可促进炎症并导致影响屏障部位的炎性疾病。我们以前可以表明，肠道2型ILC（ILC2）在蠕虫感染中的保护功能主要取决于脂肪酸代谢和FAO，而葡萄糖则是次要的。研究控制气道炎症中致病性ILC2功能的代谢途径，我们发现获得外部葡萄糖和脂质用于增殖是慢性激活的先决条件。通过给小鼠喂食生酮饮食使宿主偏向分解代谢脂质代谢和脂肪酸氧化（FAO），消除了ILC2介导的气道炎症。在这项提案中，我们的目标是确定分子中继调节保护性和致病性ILC2反应之间的代谢开关。我们建议，这样的继电器是由核受体调节宿主的饮食状况和控制细胞内在的代谢ILC2。为了研究我们的假设，我们将寻找在生酮饮食中上调并控制分解代谢FA代谢的候选核受体，我们发现可以防止诱导致病性ILC2反应。我们将测试我们的候选物在蠕虫感染的背景下代谢控制保护性肠ILC2并预防气道炎症中致病性ILC2的发展。总的来说，研究和鉴定介导从致病性到保护性ILC2反应的转换的机制提供了一种以前未探索的治疗慢性炎症的方法。因此，通过我们的研究，我们的目标是解决一个主要的社会挑战，即西方世界慢性炎症性疾病的急剧增加，并确定治疗干预的新靶点。

Innate lymphoid cells (ILC) serve the major task of protection and maintenance of the tissue barrier. However, chronic activation of ILC can promote inflammation and contribute to inflammatory disorders affecting barrier sites. We could previously show that the protective function of intestinal type 2 ILC (ILC2) in helminth infections critically depends on fatty acid FA metabolism and FAO, while glucose is dispensable. Investigating the metabolic pathways controlling the function of pathogenic ILC2 in airway inflammation we discovered that the acquisition of external glucose and lipids for proliferation as a prerequisite for chronic activation. Skewing the host towards catabolic lipid metabolism and fatty acid oxidation (FAO) by feeding mice a ketogenic diet ablated ILC2-mediated airway inflammation. In this proposal we aim to identify the molecular relay regulating the metabolic switch between protective and pathogenic ILC2 responses. We propose that such relays are represented by nuclear receptors regulated by the dietary status of the host and controlling cell intrinsic metabolism in ILC2. To investigate our hypothesis we will search for candidate nuclear receptors upregulated in ketogenic diet and in control of catabolic FA metabolism, we found to prevent the induction of pathogenic ILC2 responses. We will test our candidate(s) to metabolically control protective intestinal ILC2 in the context of helminth infection and prevent the development of pathogenic ILC2 in airway inflammation. Overall, investigating and identifying mechanisms mediating a switch from pathogenic to protective ILC2 responses offers a previously unexplored approach to treat chronic inflammation. Thus with our research we aim to the tackle one major societal challenge, the dramatic increase in chronic inflammatory disorders in the Western World and to identify novel targets for therapeutic intervention.