“Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels

Macrophages reside in virtually every organ. First arising during embryogenesis, macrophages replenish themselves in the adult through a combination of self-renewal and influx of bone marrow-derived monocytes. As large phagocytic cells, macrophages participate in innate immunity while contributing to tissue-specific homeostatic functions. Among the key metabolic tasks are senescent red blood cell recycling, free heme detoxification, and provision of iron for de novo hemoglobin synthesis. While this systemic mechanism involves the shuttling of iron between spleen, liver, and bone marrow through the concerted function of defined macrophage populations, similar circuits appear to exist within the microenvironment of other organs. The high turnover of iron is the prerequisite for continuous erythropoiesis and tissue integrity but challenges macrophages’ ability to maintain cellular iron homeostasis and immune function. This review provides a brief overview of systemic, microenvironmental, and cellular aspects of macrophage iron handling with a focus on exciting and unresolved questions in the field.