Abstract
ABSTRACTSerum lactate levels are traditionally interpreted as a marker of tissue hypoxia and often used clinically as an indicator of severity and outcome of sepsis/septic shock. Interestingly, recent studies involving the effects of tumor-derived lactate suggest that lactate itself may have an immunosuppressive effect in its local environment. This finding adds to the recent advances in immunometabolism that shed light on the importance of metabolism and metabolic intermediates in the regulation of innate immune and inflammatory responses in sepsis. In this article, we summarize recent studies, showing that the activation of immune cells requires aerobic glycolytic metabolism and that lactate produced by aerobic glycolysis may play an immunosuppressive role in sepsis.
Highlights
Sepsis is a clinical syndrome characterized by systemic inflammatory response to infection [1,2,3]
Payen, and Pickkers as well as others recently hypothesized that an immunosuppressive phase may exist in sepsis/septic patients [3, 9,10,11,12,13,14,15] and may alternatively be a better candidate for therapy [16, 17]. This hypothesis seems controversial [18, 19], there are number of factors that contribute to immunosuppression, including the apoptosis of innate immune cells
Recent studies have shown that metabolic enzymes and their products can stimulate the release of alarmins from cells [46], act as bacterial component receptors [47], promote epigenetic modification of histones for trained immunity [48], regulate microRNA expression [49], and participate in various other immunoregulatory processes. These findings suggest that the transient adoption of aerobic glycolysis in the immune response may play an active role in regulating cell phenotype [50]
Summary
Sepsis is a clinical syndrome characterized by systemic inflammatory response to infection [1,2,3]. Recent studies have shown that metabolic enzymes and their products can stimulate the release of alarmins from cells [46], act as bacterial component receptors [47], promote epigenetic modification of histones for trained immunity [48], regulate microRNA expression [49], and participate in various other immunoregulatory processes These findings suggest that the transient adoption of aerobic glycolysis in the immune response may play an active role in regulating cell phenotype [50]. Recent studies have reported that the addition of exogenous lactate to growth medium containing DCs induced metabolic reprogramming and triggered innate immune cells to adapt a more tolerogenic phenotype [73, 74] These authors proposed that the unfavorable concentration gradient of lactate may prevent its diffusion-mediated export from immunogenic DCs that rely on aerobic glycolysis. Theoretically they may not be susceptible to this type of metabolic regulation
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