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Cell. 2017 Jun 15;169(7):1263-1275.e14. doi: 10.1016/j.cell.2017.05.031.

Metabolic Adaptation Establishes Disease Tolerance to Sepsis.

Author information

1
Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal; Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07747 Jena, Germany.
2
Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
3
Language and Information Engineering Laboratory, Friedrich-Schiller-University, 07743 Jena, Germany.
4
INSERM U1213, Université Claude Bernard Lyon, 69100 Villeurbanne, France.
5
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07747 Jena, Germany; Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany.
6
Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal. Electronic address: mpsoares@igc.gulbenkian.pt.

Abstract

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.

KEYWORDS:

disease tolerance; ferritin; gluconeogenesis; glucose-6-phosphatase; heme; infection; inflammation; iron; metabolism; sepsis

PMID:
28622511
PMCID:
PMC5480394
DOI:
10.1016/j.cell.2017.05.031
[Indexed for MEDLINE]
Free PMC Article

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