Iron Regulatory Protein (Irp)-Mediated Iron Homeostasis Is Critical for Neutrophil Development and Differentiation in the Bone Marrow

Abstract

Iron is mostly devoted to the hemoglobinization of erythrocytes for oxygen transport. Yet, emerging evidence points to a broader role for the metal in hematopoiesis, including the formation of the immune system. Iron availability in mammalian cells is controlled by iron-regulatory proteins (IRP)-1 and -2. We report that global disruption of both IRP1 and IRP2 in adult mice impairs neutrophil development and differentiation in the bone marrow, yielding immature neutrophils with abnormally high glycolytic and autophagic activity, resulting in neutropenia. IRPs promote neutrophil differentiation in a cell intrinsic manner by securing cellular iron supply together with transcriptional control of neutropoiesis to facilitate differentiation to fully mature neutrophils. Unlike neutrophils, monocyte count was not affected by IRP and iron deficiency, suggesting a lineage-specific effect of iron on myeloid output. This study unveils the previously unrecognized importance of IRPs and iron metabolism in the formation of a major branch of the innate immune system.

Biodegradable Ferric Phosphate Nanocarriers with Tumor‐Specific Activation and Glutathione Depletion for Tumor Self‐Enhanced Ferroptosis and Chemotherapy

“…[7] Iron regulatory proteins (IRP1 and IRP2) are responsible for maintaining the intracellular iron homeostasis by regulating the concentration of iron in cells. [8,9] As most of the iron is stored in ferritin or holotransferrin, there is very little free iron in the normal cells. In order to achieve tumor ferroptosis, it is necessary to actively provide free iron to tumor cells, because excess free iron can trigger ferroptosis through iron-mediated Fenton reaction to produce cytotoxic reactive oxygen species (ROS) and subsequent lipid peroxidation under the action of lipoxygenase.…”

MXene‐Mediated Catalytic Redox Reactions for Biomedical Applications

“…[5] Among the diverse metal ions that catalyze the ROS generation, Fe 2 + possesses the unique Fenton catalytic capacity to convert H 2 O 2 into extremely reactive •OH. [6] To avoid abnormal •OH activity, cells therefore regulate multiple biomolecules and biofunctions (e. g., hepcidin, [7] iron-sulfur cluster, [8] and iron regulatory protein [9] ) to maintain iron homeostasis for dynamic redox homeostasis.…”