W100 - Cellular Iron Is a Critical Regulator of ILC2 Metabolic Function and Development of Airway Hyperreactivity

Yoshihiro Sakano – University of Southern California; Stephen Shen – University of Southern California; Mohammad Kazemi – University of Southern California; Kei Sakano – University of Southern California; Xin Li – University of Southern California; Omid Akbari – University of Southern California

Abstract Text: Iron is a critical nutritional trace element. With many of the mechanisms involved in systemic iron homeostasis characterized however, attention is now increasingly turning to the role of iron in tissues and immune cells. Notably, iron has been known as a critical regulator of cellular processes, as iron deficiency impairs multiple aspects of T cell responses. Our research indicates that iron plays a pivotal role on the function of group 2 innate lymphoid cells (ILC2s), which rapidly induce a type 2 inflammation in the lungs in response to allergen exposure. Transferrin receptor 1 (TfR1) is rapidly upregulated and functional during ILC2 activation in the lungs, 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 restriction of cellular iron availability reduces the development of airway hyperreactivity in experimental models of ILC2-driven allergic asthma. We confirmed the effects of iron on human ILC2s, as both iron uptake blockade and deprivation abrogate ILC2 effector functions in ILC2s isolated from healthy subjects. In a clinical setting, we found a negative relation between the levels of TfR1 expression on circulating ILC2s and the severity of allergic asthma in cohorts of healthy, mild, moderate or severe patients with asthma, suggesting that the expression of TfR1 and iron may directly be linked to the severity of asthma. Collectively, our studies define cellular iron as a critical regulator of ILC2 function and magnitude of type 2 airway inflammation.