Metabolic Adaptation Establishes Disease Tolerance to Sepsis

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2017 Jun 17

PMID 28622511

Citations 138

Authors

Sebastian Weis

Ana Rita Carlos

Maria Raquel Moita

Sumnima Singh

Birte Blankenhaus

Silvia Cardoso

Rasmus Larsen

Sofia Rebelo

Sascha Schauble

Laura Del Barrio

Gilles Mithieux

Fabienne Rajas

Sandro Lindig

Michael Bauer

Miguel P Soares

Affiliations

Soon will be listed here.

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.

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