Pathophysiological mechanisms of AI. Systemic inflammation results in immune cell activation and formation of numerous cytokines. Interleukin (IL-6) and IL-1β, as well as lipopolysaccharide (LPS), are potent inducers of the master regulator of iron homeostasis, hepcidin, in the liver, whereas expression of the iron-transport protein transferrin is reduced. Hepcidin causes iron retention in macrophages by degrading the only known cellular iron exporter ferroportin (FP1); by the same mechanism, it blocks dietary iron absorption in the duodenum. Multiple cytokines (eg, interleukin-1β [IL-1β], IL-6, IL-10, and interferon-γ [IFN-γ]) promote iron uptake into macrophages, increase radical-mediated damage to erythrocytes and their ingestion by macrophages, and cause efficient iron storage by stimulating ferritin production and blocking iron export by transcriptional inhibition of FP1 expression. This results in the typical changes of AI (ie, hypoferremia and hyperferritinemia). In addition, IL-1 and TNF inhibit the formation of the red cell hormone erythropoietin (Epo) by kidney epithelial cells. Epo stimulates erythroid progenitor cell proliferation and differentiation, but the expression of its erythroid receptor (EpoR) and EpoR-mediated signaling are inhibited by several cytokines. Moreover, cytokines can directly damage erythroid progenitors or inhibit heme biosynthesis via radical formation or induction of apoptotic processes. Importantly, because of iron restriction in macrophages, the availability of this metal for erythroid progenitors is reduced. Erythroid progenitors acquire iron mainly via transferrin-iron/transferrin receptor (Tf/TfR)-mediated endocytosis. Erythroid iron deficiency limits heme and hemoglobin (Hb) biosynthesis, as well as reduces EpoR expression and signaling via blunted expression of Scribble (Scb). In addition, the reduced Epo/EpoR signaling activity impairs the induction of erythroferrone (Erfe), which normally inhibits hepcidin production.