Duodenal macrophages control dietary iron absorption via local degradation of transferrin

Iron is an essential cellular metal that is important for many physiological functions including erythropoiesis and host defense. It is absorbed from the diet in the duodenum and loaded onto transferrin, the main iron transport protein. Inefficient dietary iron uptake promotes many diseases, but mechanisms regulating iron absorption remain poorly understood. By assessing mice that harbor a macrophage-specific deletion of the tuberous sclerosis complex 2 (Tsc2), a negative regulator of mTORC1, we found that these mice possessed various defects in iron metabolism including defective steady state erythropoiesis and a reduced saturation of transferrin with iron. This iron-deficiency phenotype was associated with an iron import block from the duodenal epithelial cells into the circulation. Activation of mTORC1 in villous duodenal CD68+ macrophages induced serine protease expression and promoted local degradation of transferrin, whereas depletion of macrophages in mice increased transferrin levels. Inhibition of mTORC1 with everolimus or serine protease activity with nafamostat restored transferrin levels in the Tsc2-deficient mice as well as transferrin saturation. Physiologically, transferrin levels were regulated in the duodenum during the prandial process and Citrobacter rodentium infection. These data suggest that duodenal macrophages determine iron transfer to the circulation by controlling transferrin availability in the lamina propria villi.