Neutrophil dysfunction in β-thalassemia. In WT mice (A), neutrophils mature normally and are released into peripheral blood. Similarly, in the spleen, the majority of neutrophils are mature, and efficiently phagocytose and kill bacteria (yellow dots), along with production and release of abundant ROS. Macrophages intricately interact with neutrophils to resolve the infection. In older mice with β-thalassemia (B) that have developed iron overload, BM neutrophils are normal, but in peripheral blood and spleen, immature neutrophils accumulate. In the spleen, these immature neutrophils have decreased Pu.1 expression, fail to upregulate Pu.1 upon activation by bacterial infection, and produce deficient levels of ROS. They fail to phagocytose bacteria, and mice succumb to infection. Meanwhile, macrophages in the spleen are iron loaded (indicated by black dots) and may compound the deficiencies in the innate immune system observed in patients with β-thalassemia.⁹