The importance of lipid metabolism for the maintenance of pathogenic ILC2 responses

在过去的几十年里，免疫性疾病的流行病学在西方世界发生了很大的变化。许多传染病的逐渐根除与包括哮喘和克罗恩病在内的慢性炎性疾病的增加相一致。绝大多数慢性疾病无法治愈，目前的治疗策略主要针对急性免疫反应。然而，长寿命记忆免疫细胞的重新激活可能会导致复发性耀斑，从而导致慢性炎症。因此，更好地了解促进免疫细胞寿命的因素可能会指导预防和治疗措施。先天性淋巴样细胞（ILC）的主要功能是保护和维持组织屏障。然而，II型ILC（ILC 2）特定亚型的慢性激活是哮喘的主要驱动因素。在鉴定致病性ILC 2中活性代谢途径以治疗过敏原驱动的气道炎症的努力中，我们发现外部获得的脂质驱动ILC 2的增殖和慢性激活。外部获得的脂肪酸必须暂时储存在脂滴中以防止脂毒性，并且增加的脂质摄取和储存由葡萄糖的总体可用性控制。我们进一步发现，给小鼠喂食生酮饮食，从而限制饮食中葡萄糖的可用性，通过损害葡萄糖和脂肪酸代谢以及ILC 2中脂滴的形成，在很大程度上消除了ILC 2介导的气道炎症。引人注目的是，脂质的储存和随后通过脂肪酸的氧化产生能量是长寿记忆T细胞的一般特征，并且对于它们的维持和存活至关重要。因此，我们提出，在过敏原驱动的气道炎症的背景下，脂质的获得增加是促进“记忆样”ILC 2反应长期维持的重要先决条件。我们假设致病性ILC 2的维持和存活关键取决于ILC 2获取、储存和利用外部脂质的能力，并提出靶向ILC 2中的脂质代谢代表了一种未探索的治疗已建立的慢性气道炎症的方法。为了解决这些问题，我们将研究a）记忆样ILC 2应答的代谢调节和B）测试IL-9诱导针对ILC 2长期存活定制的代谢程序的重要性。此外，我们将测试c）脂质代谢对于致病性ILC 2应答的长期维持的功能和d）研究生酮饮食或维生素A缺乏饮食靶向已建立的慢性气道炎症的代谢维持的功效。总的来说，研究和确定气道炎症中ILC 2长期存活和维持的代谢调节机制提供了一种以前未探索的方法来应对慢性炎症性疾病日益严重的公共卫生问题。

Over the last decades the epidemiology of immune diseases has changed considerably in the Western World. The gradual eradication of many infectious diseases coincides with an increase of chronic inflammatory conditions including asthma and Crohn’s disease. The vast majority of chronic diseases cannot be cured and current treatment strategies predominately target the acute immune response. However, reactivation of long-lived memory immune cells may cause recurrent flares resulting in chronic inflammation. Thus, a better understanding of the factors promoting longevity of immune cells may guide measures of prevention and cures. The major function of innate lymphoid cells (ILC) is the protection and maintenance of the tissue barrier. However, chronic activation of a specific subtype of ILC type II (ILC2) is a major driver of asthma. In an effort to identify metabolic pathways active in pathogenic ILC2 to treat allergen-driven airway inflammation we found that externally acquired lipids drive proliferation and chronic activation of ILC2. Externally acquired fatty acids must be transiently stored in lipid droplets to prevent lipotoxicity and the increased lipid uptake and storage is controlled by the overall availability of glucose. We further discovered that feeding mice a ketogenic diet and thus restricting the availability of dietary glucose largely ablated ILC2-mediated airway inflammation by impairing both glucose and fatty acid metabolism and the formation of lipid droplets in ILC2. Strikingly, storage of lipids and subsequent energy generation through oxidation of fatty acids is a general feature of long-lived memory T cells and essential for their maintenance and survival. Thus, we propose that increased acquisition of lipids in the context of allergen-driven airway inflammation is an important prerequisite facilitating the long-term maintenance of ‘memory-like’ ILC2 responses. We hypothesize that the maintenance and survival of pathogenic ILC2 critically depends on the capacity of ILC2 to acquire, store and utilize external lipids and propose that targeting lipid metabolism in ILC2 represents an unexplored approach to treat established chronic airway inflammation. To address these questions we will investigate a) the metabolic regulation of memory-like ILC2 responses and b) test the importance of IL-9 to induce a metabolic program tailored towards the long-term survival of ILC2. Further, we will test c) the function of lipid metabolism for the long-term maintenance of pathogenic ILC2 responses and d) investigate the efficacy of ketogenic diet or vitamin A deficient diets to target the metabolic maintenance of established chronic airway inflammation. Overall, investigating and identifying mechanisms of metabolic regulation for the long-term survival and maintenance of ILC2 in airway inflammation offers a previously unexplored approach to encounter the growing public health problem of chronic inflammatory diseases.