Iron controls the development of airway hyperreactivity by regulating ILC2 metabolism and effector function

Group 2 innate lymphoid cells (ILC2s) rapidly induce a type 2 inflammation in the lungs in response to allergens. Here, we focused on the role of iron – a critical nutritional trace element – on ILC2 function and asthma pathogenesis. In the lungs, transferrin receptor 1 (TfR1) is rapidly upregulated and functional during ILC2 activation, while blocking transferrin uptake reduces ILC2 expansion and activation. Iron deprivation reprograms ILC2 metabolism, inducing a HIF-1a-driven upregulation of glycolysis and inhibition of oxidative mitochondrial activity. Consequently, in vivo iron chelation or induction of hypoferremia notably reduces the development of airway hyperreactivity in experimental models of ILC2-driven allergic asthma. Human circulating ILC2s rapidly induce TfR1 during activation, while iron deprivation reduces effector functions. Finally, we found a negative relation between circulating ILC2 TfR1 expression and airway function in cohorts of patients with asthma. Collectively, our studies define cellular iron as a critical regulator of ILC2 function. Overall design: Activated lung ILC2s were FACS sorted and cultured with an iron chelator for 18h after which culture was supplemented or not with iron for an additional 8 hours.2型固有淋巴细胞（Group 2 innate lymphoid cells, ILC2s）可在过敏原刺激下快速在肺部诱发2型炎症反应。本研究聚焦于铁——一种关键的营养微量元素——对2型固有淋巴细胞功能与哮喘发病机制的调控作用。在肺部中，转铁蛋白受体1（transferrin receptor 1, TfR1）在2型固有淋巴细胞活化过程中会快速上调并发挥功能；而阻断转铁蛋白摄取则会抑制2型固有淋巴细胞的扩增与活化。铁缺乏会重编程2型固有淋巴细胞的代谢模式，诱导由缺氧诱导因子1α（hypoxia-inducible factor 1α, HIF-1α）介导的糖酵解上调，并抑制线粒体氧化活性。因此，在2型固有淋巴细胞介导的过敏性哮喘实验模型中，体内铁螯合处理或诱导低铁血症可显著降低气道高反应性的发生发展。人类循环中的2型固有淋巴细胞在活化过程中会快速上调转铁蛋白受体1的表达，而铁缺乏则会削弱其效应功能。最后，我们在哮喘患者队列中发现，循环2型固有淋巴细胞的转铁蛋白受体1表达水平与气道功能呈负相关。综上，本研究证实细胞内铁是调控2型固有淋巴细胞功能的关键因子。实验设计概况：将活化的肺部2型固有淋巴细胞通过荧光激活细胞分选术（fluorescence-activated cell sorting, FACS）分离纯化，经铁螯合剂培养18小时后，再向培养基中补充或不补充铁离子，继续培养8小时。