Frontline Science: Endotoxin-induced immunotolerance is associated with loss of monocyte metabolic plasticity and reduction of oxidative burst

Abstract

Secondary infections are a major complication of sepsis and associated with a compromised immune state, called sepsis-induced immunoparalysis. Molecular mechanisms causing immunoparalysis remain unclear; however, changes in cellular metabolism of leukocytes have been linked to immunoparalysis. We investigated the relation of metabolic changes to antimicrobial monocyte functions in endotoxin-induced immunotolerance, as a model for sepsis-induced immunoparalysis. In this study, immunotolerance was induced in healthy males by intravenous endotoxin (2 ng/kg, derived from Escherichia coli O:113) administration. Before and after induction of immunotolerance, circulating CD14 + monocytes were isolated and assessed for antimicrobial functions, including cytokine production, oxidative burst, and microbial (Candida albicans) killing capacity, as well metabolic responses to ex vivo stimulation. Next, the effects of altered cellular metabolism on monocyte functions were validated in vitro. Ex vivo lipopolysaccharide stimulation induced an extensive rewiring of metabolism in naive monocytes. In contrast, endotoxin-induced immunotolerant monocytes showed no metabolic plasticity, as they were unable to adapt their metabolism or mount cytokine and oxidative responses. Validation experiments showed that modulation of metabolic pathways, affected by immunotolerance, influenced monocyte cytokine production, oxidative burst, and microbial (C. albicans) killing in naive monocytes. Collectively, these data demonstrate that immunotolerant monocytes are characterized by a loss of metabolic plasticity and these metabolic defects impact antimicrobial monocyte immune functions. Further, these findings support that the changed cellular metabolism of immunotolerant monocytes might reveal novel therapeutic targets to reverse sepsis-induced immunoparalysis. K E Y W O R D Sendotoxemia, endotoxin tolerance, immunometabolism, immunoparalysis, monocytes, sepsis Abbreviations: 2DG, 2-deoxy-D-glucose; 6AN, 6-aminonicotinamide; AUC, area under the curve; BPTES bis-2-(5-phenylacetamido-1,3,4-, bis-2-(5-phenylacetamido-1

Phagocytosis–Inflammation Crosstalk in Sepsis: New Avenues for Therapeutic Intervention

“…A recent study using a human in vivo model of endotoxemia, however, showed that ET monocytes cannot induce an oxidative response to Escherichia coli or Candida albicans challenge. This effect was due to a failure of ET monocytes to modify their metabolism during ex vivo LPS restimulation, resulting in reduced Candida killing capacity ( 54 ). However, as most of these studies used different protocols to induce ET, both in vivo and ex vivo , the unambiguous interpretation of the process remains challenging.…”

Animal-Free Human Whole Blood Sepsis Model to Study Changes in Innate Immunity

“…For example, the exact exposure time and the amount of pathogens within the blood during sepsis cannot be determined with certainty. Therefore, as another alternative, injection of immune-stimulants, including lipopolysaccharide (LPS), has been performed and investigated in healthy human volunteers ( 8 – 10 ). On the one hand, this approach provides the intriguing opportunity to study the immunological response directly in human organisms.…”

Current Understanding of Innate Immune Cell Dysfunction in Childhood Undernutrition

“…Maintaining metabolic plasticity is necessary for immune cells to generate anti-pathogen responses when challenged and this appears to be compromised in immunoparalysed cells. For example, monocytes from healthy adults injected with endotoxin have a less pronounced metabolic response to re-stimulation with endotoxin and an associated reduction in pathogen killing in vitro 7 hours post-injection relative to monocytes isolated from donors without pre-exposure to endotoxin (31). Trained immunity may be one mechanism by which innate immune cells adapt to the simultaneous derangement of microbial and nutrient exposures during undernutrition.…”

“…Trained immunity may be one mechanism by which innate immune cells adapt to the simultaneous derangement of microbial and nutrient exposures during undernutrition. Children with SAM share many of the clinical features of sepsis, which is a common clinical complication of SAM and a recognized stimulus for monocyte training (31–33). During sepsis, epigenetic modifications in monocytes down-regulate pro-inflammatory cytokine production but upregulate alternative functional genes, including antimicrobial peptides (AMP) (32, 33).…”