LAUSR

The quest for discovering novel therapeutics to treat acute inflammatory conditions such as sepsis has been a significant challenge for scientists and physicians. Despite promising discoveries using animal models, innumerable clinical trials have failed to yield any definitive treatment to reduce morbidity and mortality associated with human sepsis. There is a critical need to better understand the cellular and molecular pathogenesis of sepsis and other acute inflammatory conditions and explore novel therapies to improve outcomes. As such, the field of immunometabolism is being widely explored to better understand themetabolic basis for activation and resolution of inflammation in a quest to discover novel therapeutic targets. Alterations in leukocyte metabolism and subsequent changes in the concentrations of intracellular metabolites has recently emerged as one of the major mechanisms that guide immune cell responses during exposure to an inflammatory insult such a LPS.1,2 Activation of myeloid cells leads to significant intracellular accumulation of metabolic intermediates such as succinate, itaconate, citrate, and many others.2 Exploration of the signaling mechanisms mediated by these metabolic intermediates has created a paradigm shift regarding how we view the role of metabolic intermediates as drivers of leukocyte responses. These findings have uncovered a novel area of investigation that may improve our understanding of leukocyte functions during sepsis for discovering novel therapeutic targets. In this issue of the Journal of Leukocyte Biology, Zhu and colleagues report new data that provide insights into LPS-induced temporal changes in concentrations of major intracellular metabolites in THP-1 monocytic cells during periods of activation, transition, and resolution. The authors categorized post-LPS exposure periods into three sequential phases—anabolic activation (0–8 h), catabolic deactivation (24–48 h), and transition to early resolution (48–96 h). As summarized in Figure 1, the findings presented in this manuscript represents a characterization of the carbohydrate, protein, lipid, and nucleic acid metabolites induced by LPS exposure during the aforementioned sequential phases. The authors report that during the initial activation phase the concentrations of glucose-1-phosphate and fructose-1,6-bisphosphate are significantly increased implying an increase in glycogenolysis and glycolysis, respectively.3 Increased glycogenolysis was associatedwith increased UDP-glucose levels during the initial phase. This is an interesting finding as UDP-glucose can glycosylate proteins and plasma protein glycosylation patterns have been shown to be distinctly regulated in sepsis survivors versus nonsurvivors.4 Glucose-1phosphate and fructose-1,6-bisphosphate levels declined over the deactivation and resolution phases indicating a reduced rate of glycolysis and glycogenolysis over time. Despite the observed increase in glycolysis intermediates, the levels of glycolysis end products, pyruvate and lactate, remained at low levels throughout all phases. This is a perplexing finding given that high cellular lactate production and lactate accumulation are hallmarks of severe sepsis. Tracking of carbon flux using stable isotope radiolabeling to determine the exact fate of glucose as it travels via glycolysis into Krebs cycle would provide more definitive information. Zhu et al. report that the initial activation phase was not associated with an increase in pentose phosphate pathway (PPP) metabolites. This finding is in contrast to some of the previous findings that show an acute increase in flux through the PPP pathway in LPS-activated macrophages.5 The observed difference might be due to differences in cell types employed in the respective studies. Sedoheptulose7-phosphate, another metabolite of the PPP pathway, was transiently increased at the 24 h time point. Increased sedoheptulose7-phosphate, derived through the action of carbohydrate response kinase-like protein (CARKL), has previously been shown to be increased in anti-inflammatory M2 like macrophages,5 thereby supporting the authors hypothesis in the current study, implicating the role of CARKL in the induction of THP-1 cell deactivation phase. The alterations in Krebs cycle metabolic intermediates presented in this paper are in line with previous studies showing increased intracellular succinate and itaconate accumulation during the initial acute activation phase of myeloid cells.1–3 The authors state that fumarate levels were also decreased during activation, but the data were not shown in the paper. In accordance with the previous reports,1 these findings suggest potential breaks in the Krebs cycle at succinate dehydrogenase and isocitrate dehydrogenase. Previous studies had not reported the temporal changes in these metabolites after LPS exposure over a prolonged period. The current paper assumes importance in that respect and shows that the concentration of succinate continues to remain high up to 96 h after LPS exposure, whereas the concentration of itaconate peaks at 8 h and then continues to decline, reaching baseline levels by 72 h. Succinate has been shown to play a critical role in mediating hypoxia inducible factor-1α stabilization and increased mitochondrial reactive oxygen species production and increased IL-1β secretion, thereby promoting a proinflammatory