Potentiating ferroptosis as treatment of allergic airway inflammation

先天淋巴样细胞（ILC）起着保护和维持组织屏障的主要作用。然而，ILC的慢性激活可以促进炎症并导致影响屏障部位的炎症紊乱。研究控制致病性2型先天淋巴样细胞（ILC2）在气道炎症中的功能的代谢途径，我们发现获得外部脂质进行增殖是慢性激活的先决条件。然而，脂质摄取的增加也增加了细胞对脂质自由基的暴露，这可能导致非凋亡细胞死亡。为了平衡脂质过氧化的增加，ILC2在激活时上调细胞抗氧化系统的表达。因此，我们假设增加的脂质代谢驱动致病性ILC2反应需要同时平衡脂质过氧化以防止铁下沉。因此，靶向这一保护机制可能会诱导铁下垂，并阻止致病性ILC2的诱导，从而阻止慢性气道炎症的发展。为了验证我们的假设，我们将评估ILC2生物学和ILC2介导的气道炎症中亲铁和抗铁通路的功能。总之，将铁下沉作为一种促进致病性ILC2反应的机制，为治疗慢性炎症提供了一种以前未被探索的方法。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目标。

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. Investigating the metabolic pathways controlling the function of pathogenic group type 2 innate lymphoid cells (ILC2) in airway inflammation we discovered that the acquisition of external lipids for proliferation is a prerequisite for chronic activation. However, increased lipid uptake also increases the exposure of cells to lipid radicals, which can cause the non-aopototic cell death ferroptosis. To balance increased exposure to lipid peroxidation ILC2 upregulate the expression of cellular antioxidant systems upon activation. Hence we hypothesize that increased lipid metabolism driving pathogenic ILC2 responses requires the simultaneous counterbalance of lipid peroxidation to prevent ferroptosis. As a consequence, targeting this protective mechanism may induce ferroptosis and preclude the induction of pathogenic ILC2 and thus the development of chronic airway inflammation. To investigate our hypothesis we will assess the function of pro- and anti- ferroptoic pathways in ILC2 biology and ILC2-mediated airway inflammation. Overall, targeting ferroptosis as a mechanism promoting pathogenic 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.