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. We found that transferrin receptor 1 (TfR1) is rapidly up-regulated and functional during ILC2 activation in the lungs, and blocking transferrin uptake reduces ILC2 expansion and activation. Iron deprivation reprogrammed ILC2 metabolism, inducing a HIF-1α–driven up-regulation of glycolysis and inhibition of oxidative mitochondrial activity. Consequently, we observed that in vivo iron chelation or induction of hypoferremia reduced the development of airway hyperreactivity in experimental models of ILC2-driven allergic asthma. Human circulating ILC2s rapidly induced TfR1 during activation, whereas inhibition of iron uptake or iron deprivation reduced effector functions. Last, we found a negative relationship 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.

中文翻译：

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铁通过调节 ILC2 代谢和效应器功能来控制气道高反应性的发展

第 2 组先天淋巴细胞 (ILC2) 响应过敏原，迅速诱发肺部 2 型炎症。在这里，我们重点关注铁（一种重要的营养微量元素）对 ILC2 功能和哮喘发病机制的作用。我们发现，在肺部 ILC2 激活过程中，转铁蛋白受体 1 (TfR1) 迅速上调并发挥功能，阻断转铁蛋白摄取可减少 ILC2 的扩增和激活。缺铁重新编程了 ILC2 代谢，诱导 HIF-1α 驱动的糖酵解上调并抑制线粒体氧化活性。因此，我们观察到，在 ILC2 驱动的过敏性哮喘实验模型中，体内铁螯合或诱导低铁血症可减少气道高反应性的发展。人类循环ILC2在激活过程中迅速诱导TfR1，而抑制铁摄取或铁缺乏会降低效应器功能。最后，我们发现哮喘患者中循环 ILC2 TfR1 表达与气道功能之间存在负相关。总的来说，我们的研究将细胞铁定义为 ILC2 功能的关键调节因子。