Iron-related mechanisms contributing to the generation of AI. (A) In circulation, pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) activate myeloid cells leading to the production of proinflammatory cytokines. (B) Hepatocyte stimulation with proinflammatory cytokines, especially IL-6 and IL-1β, and PAMPs stimulates the expression of the liver iron hormone hepcidin, which promotes autocrine and paracrine iron retention due to the degradation of the iron exporter FPN. Kupffer cell stimulation with proinflammatory cytokines, PAMPs and DAMPs further feeds cytokine-mediated hepcidin upregulation in the liver. (C) Increased hepcidin levels in circulation block dietary iron import by degrading FPN. Local intestinal inflammation promotes HIF-2α (hypoxia-inducible factor 2α) stabilization and duodenal cytochrome b (DCYTB)/divalent iron transporter 1 (DMT1)–mediated iron absorption and may alter the composition of the intestinal microbiota. (D) In the spleen, where macrophages turn over large amounts of iron owing to the recycling of RBCs, iron accumulates in response to cytokines, hepcidin, PAMPs, and DAMPs, which decreases FPN-mediated iron export and affects additional pathways that cause iron retention. (E) Macrophage iron retention and decreased iron absorption reduce plasma iron levels and limit iron availability for erythroid progenitors, where iron is required for heme biosynthesis. As a consequence, anemia develops. Fe, iron; Fe-Tf, iron transferrin; TNF, tumor necrosis factor.