Metabolic reprogramming and tolerance during sepsis-induced AKI

Key Points Resistance and tolerance mechanisms govern the infection response and determine host survival A switch to Warburg metabolism seems to be an important survival strategy in immune cells and possibly in tubular epithelial cells in response to inflammation Reprogramming of metabolic pathways is a key cellular strategy to execute resistance and tolerance protective programmes Early metabolic reprogramming in the response to inflammation is crucial to determine the acute response of the cell, to avoid cell death and to determine the repair phenotype during recovery Understanding of resistance and tolerance mechanisms in sepsis might provide a basis for the development of therapeutic strategies to prevent or reverse organ damage, promote recovery and decrease mortality Decreasing susceptibility to tissue damage — a protective strategy known as tolerance — might be as important as infection resistance in determining outcomes in sepsis. Here, the authors discuss tolerance mechanisms that act in the kidney during sepsis, with a focus on the role of metabolic reprogramming. The host defence against infection is an adaptive response in which several mechanisms are deployed to decrease the pathogen load, limit tissue injury and restore homeostasis. In the past few years new evidence has suggested that the ability of the immune system to limit the microbial burden — termed resistance — might not be the only defence mechanism. In fact, the capacity of the host to decrease its own susceptibility to inflammation- induced tissue damage — termed tolerance — might be as important as resistance in determining the outcome of the infection. Metabolic adaptations are central to the function of the cellular immune response. Coordinated reprogramming of metabolic signalling enables cells to execute resistance and tolerance pathways, withstand injury, steer tissue repair and promote organ recovery. During sepsis-induced acute kidney injury, early reprogramming of metabolism can determine the extent of organ dysfunction, progression to fibrosis, and the development of chronic kidney disease. Here we discuss the mechanisms of tolerance that act in the kidney during sepsis, with particular attention to the role of metabolic responses in coordinating these adaptive strategies. We suggest a novel conceptual model of the cellular and organic response to sepsis that might lead to new avenues for targeted, organ-protective therapies.