New functions for an iron storage protein: the role of ferritin in immunity and autoimmunity

Ferritin is a ubiquitous and specialised protein involved in the intracellular storage of iron; it is also present in serum and other biological fluids, although its secretion processes are still unclear. We here review evidence supporting the hypothesis that macrophages play a role in the production and secretion of extracellular ferritin, as well as evidence supporting a novel function as a signalling molecule and immune regulator. In particular, H-ferritin, which inhibits the proliferation of lymphoid and myeloid cells, may be regarded as a negative regulator of human and murine hematopoiesis. The idea that it also acts as a signalling protein has been supported by the cloning and characterisation of the specific H-ferritin receptor TIM-2, a member of the TIM gene family. A number of studies of the mouse TIM gene family indicate that this protein plays an important role in immune-mediated diseases. This last finding, together with the fact that ferritin acts as an immuno-suppressor, has allowed us to formulate hypotheses regarding the possible role of alterations of H-ferritin/TIM-2 binding/signalling in the pathogenesis of autoimmune diseases.