Dr. Rivella and his team found that a third player is essential: macrophages, the immune cells that engulf cellular garbage and pathogens. Macrophages had been known to digest the iron left when old blood cells are targeted for destruction, but Dr. Rivella discovered that they also are necessary for stress erythropoiesis. He found macrophages need to physically touch erythroblasts, the factories that make red blood cells, in order for more factories to be created so that they can churn out red blood cells.
"No one knew macrophages were a part of emergency red blood cell production. We now know they provide fuel to push red blood cell factories to work faster," says the study's lead author Dr. Pedro Ramos, a former postdoctoral researcher at Weill Cornell [...]
Iron control is regulated, first and foremost, by hepcidin or Hamp, a hormone secreted into the bloodstream by the liver. Hamp controls the so-called "iron gate" in the intestines, a protein known as ferroportin. Ferroportin allows the body to absorb iron from food to help make red blood cells. (Iron latches on to the oxygen that the blood cells carry.) If iron levels are too high from iron-rich foods that are consumed, Hamp levels increase, which shuts the door on ferroportin's iron gate, blocking iron absorption, says Weill Cornell's Dr. Carla Casu, a postdoctoral researcher in Dr. Rivella's laboratory and one of the two lead authors of this study with Dr. Guo at Isis Pharmaceuticals. Patients with beta-thalassemia and hemochromatosis have levels of Hamp that are too low, so the body absorbs more iron than is healthy. Hemochromatosis occurs because of a deficit in the HFE gene that controls the Hamp hormone. "Hamp is sleeping. It doesn't wake up when iron comes along, so too much iron is absorbed," says Dr. Rivella. The defect in beta-thalassemia is due to a defect in the globin gene that helps make hemoglobin. So Hamp is shut down because the body senses the anemia, and believes that more iron is required to make red cells. As a result, there is iron overload." The researchers found an answer to the iron overload in both diseases by studying a third disease, a childhood disorder in which a mutation in a gene called Tmprss6 causes Hamp levels to rise too high, so not enough iron is being extracted from the diet. Tmprss6 keeps Hamp levels high during childhood and adolescence, so a body cannot use iron successfully to grow.
They reasoned that if they could create the conditions of Tmprss6 mutation—high levels of Hamp hormone and repression of the body's use of iron—in patients with thalassemia and hemochromatosis, they could treat those conditions. "If we block Tmprss6, we increase the expression of Hamp to normal levels, with the consequence that iron does not now accumulate," Dr. Monia says.
