Iron-mediated control of glucose metabolism is central to promote disease tolerance to polymicrobial infections

Iron is a redox-active transition metal that has a central role in a variety of biological processes, which include energy production, oxygen transport and storage as well as metabolism. Despite being critical for organismal homeostasis, deregulation of iron metabolism is often associated with disease. Here we demonstrate that induction of the iron sequestering ferritin H chain (FTH) is critical to establish disease tolerance to sepsis, an often-lethal syndrome resulting from a maladaptive immune and metabolic response to infection. The protective effect of FTH acts via a mechanism that counters iron-driven oxidative inhibition of the liver Glucose-6-Phosphatase (G6Pase) and in doing so sustains endogenous glucose production via liver gluconeogenesis and maintains normal blood glucose levels. Our study also shows that heme, an iron protoporphyrin, is a key element in the regulation of G6Pase both in vivo and in vitro. We show that heme, in combination or not with TNF, acts via a mechanism that represses G6Pase transcription, a phenomenon countered by FTH overexpression. In conclusion, iron sequestration by FTH is critical to prevent the deregulation of host glucose underlying the development of metabolic and energetic failure associated with sepsis.