Metabolic Adaptation Establishes Disease Tolerance to Sepsis

摘要

class="head no_bottom_margin" id="sec1title">IntroductionThe pathologic outcome of infections is a direct consequence of the extent of metabolic dysfunction and damage imposed to tissues that sustain host homeostasis (, , ). Disease tolerance is a defense strategy that limits the pathologic outcome of infections without interfering directly with the host's pathogen load (). This defense strategy relies on tissue damage control mechanisms that preserve the functional output of parenchymal tissues, maintaining homeostatic parameters within a dynamic range compatible with host survival (, , ).Sepsis is a clinical syndrome, affecting ∼19 million individuals per year worldwide, characterized by a maladaptive host response with ensuing organ dysfunction. Despite tremendous efforts during the last decades, no specific therapy for sepsis exists. Increasing rates of antimicrobial resistance and lack of novel antimicrobials adds to the problem and substantiates the urgent need of innovative therapeutic options ().The pathogenesis of sepsis is only partially explained by unfettered inflammation while metabolic deregulation, leading to organ dysfunction and eventually to organ failure, is increasingly recognized as an important component of this process (). While the mechanisms underlying the inflammatory response that characterizes the pathogenesis of sepsis are fairly well understood, those driving metabolic deregulation and multi-organ dysfunction or failure remain elusive (, ).Systemic infections, including those leading to sepsis, are coupled to a host metabolic response restraining invading pathogens from accessing iron (). The large majority of iron available to pathogens is contained within the prosthetic heme groups of hemoproteins, among which hemoglobin holds the largest reservoir (). Upon hemolysis, extracellular hemoglobin is oxidized and releases heme (, ), eventually leading to the accumulation of labile heme in plasma (i.e., metabolic active heme that is loosely bound to a variety of plasma molecules). Accumulation of labile heme in plasma plays a central role in the pathogenesis of sepsis (href="#bib25" rid="bib25" class=" bibr popnode">Larsen et al., 2010). This is countered by the induction heme-catabolism by heme oxygenase-1 (HO-1), which contributes critically to the establishment of disease tolerance to sepsis (href="#bib25" rid="bib25" class=" bibr popnode">Larsen et al., 2010). As a trade-off, however, heme catabolism by HO-1 generates labile iron that can catalyze the production of reactive oxygen species via Fenton chemistry, eventually leading to oxidative stress. This is counteracted by ferritin, a heteropolymeric protein complex encoded by the ferritin heavy/heart chain (FTH) and light/liver (FTL) genes (href="#bib18" rid="bib18" class=" bibr popnode">Harrison and Arosio, 1996). Ferritin is composed of 24 FTH/FTL subunits, which can store and convert ∼4,500 atoms of Fe²⁺ into inert Fe³⁺ through the ferroxidase activity of FTH (href="#bib18" rid="bib18" class=" bibr popnode">Harrison and Arosio, 1996). The ferroxidase activity of ferritin is critical to the establishment of disease tolerance to infection in animals (href="#bib15" rid="bib15" class=" bibr popnode">Gozzelino and Soares, 2014) and plants (href="#bib7" rid="bib7" class=" bibr popnode">Deák et al., 1999). Here, we demonstrate that FTH establishes disease tolerance to sepsis via a mechanism that sustains the expression/activity of the liver G6Pase, a rate-limiting enzyme in the gluconeogenesis and glycogenolysis pathways (href="#bib31" rid="bib31" class=" bibr popnode">Mithieux, 1997, href="#bib49" rid="bib49" class=" bibr popnode">van Schaftingen and Gerin, 2002). This is required to support liver glucose production in response to systemic infections so that blood glucose levels are maintained within a dynamic physiologic range compatible with host survival, hence conferring disease tolerance to sepsis.