Iron Drives Eosinophil Differentiation in Allergic Airway Inflammation through Mitochondrial Metabolic Adaptation

Understanding the metabolic mechanisms driving eosinophil differentiation in allergic airway inflammation is imperative for developing effective asthma therapies. Despite iron's well-established involvement in various cellular processes, its role in eosinophil differentiation remains elusive. This study observed elevated intracellular iron levels during eosinophil differentiation in the context of allergic airway inflammation. Through experiments involving iron-related compounds and specific diets, we demonstrated iron's indispensable role in promoting eosinophil differentiation, both in vitro and in vivo. Remarkably, an iron chelator effectively suppressed eosinophil differentiation and alleviated allergic airway inflammation. Mechanistically, iron maintains mitochondrial metabolic activities, mTORC1 signaling, and the expression of transcription factors that enforce eosinophil differentiation. Notably, iron influx rewires specific metabolic shifts in Krebs cycle, with succinate promoting eosinophil differentiation. Overall, this study highlights the significance of understanding the regulatory role of iron and underlying metabolic mechanisms in eosinophil differentiation, providing potential metabolic intervention strategies for asthma treatment. We conducted a comparative analysis of bone marrow Granulocyte-Macrophage Progenitors (GMPs) and eosinophils to pinpoint the transcriptional programs driving iron pool expansion. Additionally, we performed RNA sequencing to contrast cytokine-stimulated eosinophils, which simulate an allergic response, with resting eosinophils through transcriptome profiling. To deepen our comprehension of how intracellular iron levels affect eosinophil differentiation, we assessed the transcriptional profile of Bone Marrow-Derived Eosinophils (BMDEs) on the seventh day following the induction of iron deficiency or iron overload.