Metabolic Adaptation Establishes Disease Tolerance to Sepsis

Summary

Sepsis is an often lethal syndrome resulting from maladaptive immune and metabolic responses to infection, compromising host homeostasis. Disease tolerance is a defense strategy against infection that preserves host homeostasis without exerting a direct negative impact on pathogens. Here, we demonstrate that induction of the iron-sequestering ferritin H chain (FTH) in response to polymicrobial infections is critical to establish disease tolerance to sepsis. The protective effect of FTH is exerted 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. This is required to prevent the development of hypoglycemia that otherwise compromises disease tolerance to sepsis. FTH overexpression or ferritin administration establish disease tolerance therapeutically. In conclusion, disease tolerance to sepsis relies on a crosstalk between adaptive responses controlling iron and glucose metabolism, required to maintain blood glucose within a physiologic range compatible with host survival.

Graphical Abstract

Highlights

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  Ferritin is required to establish disease tolerance to sepsis

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  Iron heme represses liver G6Pase during sepsis

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  Ferritin counters G6Pase repression and sustains blood glucose levels after sepsis

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  Liver gluconeogenesis is required to establish disease tolerance to sepsis

Abstract

Disease tolerance to sepsis depends on a crosstalk between iron and glucose- metabolic responses that maintain blood glucose levels within a dynamic range compatible with host survival.