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Sepsis and septic shock are associated with life-threatening organ dysfunction caused by an impaired host response to infections. Although circadian clock disturbance impairs the early inflammatory response, its impact on post-septic immunosuppression remains poorly elucidated. Here, we show that Bmal1, a core circadian clock gene, plays a role in the regulation of host immune responses in experimental sepsis. Mechanistically, Bmal1 deficiency in macrophages increases PKM2 expression and lactate production, which is required for expression of the immune checkpoint protein PD-L1 in a STAT1-dependent manner. Consequently, targeted ablation of Pkm2 in myeloid cells or administration of anti-PD-L1-neutralizing antibody or supplementation with recombinant interleukin-7 (IL-7) facilitates microbial clearance, inhibits T cell apoptosis, reduces multiple organ dysfunction, and reduces septic death in Bmal1-deficient mice. Collectively, these findings suggest that the circadian clock controls the immune checkpoint pathway in macrophages and therefore represents a potential therapeutic target for lethal infection., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Sepsis is a serious clinical disease with a high mortality rate all around the world. Liver organ dysfunction is an important sign for the severity and outcome of sepsis in patients. In this study, 1 H NMR-based metabolomics approach and biochemical assays were applied to investigate the metabolic profiling for cecal ligation and puncture (CLP) induced acute liver injury, the therapeutical effect of single/combination use of Huang-Lian-Jie-Du decoction (HLJDD) and berberine, and the interaction of them. Metabolomics analysis revealed significant perturbations in livers of septic rats, which could be ameliorated by HLJDD, berberine and their combination treatment. Berberine could better rectified glycolysis and nucleic acid metabolism in the liver. HLJDD had exceptional better anti-inflammatory, antibacterial and antioxidative effects than berberine. The interaction of berberine and HLJDD could further strengthen the anti-inflammation and anti-oxidation, but with poor effect on amino acids metabolism. These findings highlighted the feasibility of the integrated NMR based metabolomics approach to understand the pathogenesis of diseases, the action mechanisms of therapy and the herb-drug interaction., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Sepsis is the major cause of morbidity and mortality in surgical patients. Huang-Lian-Jie-Du-Decoction (HLJDD), a well-known Chinese herb formula, has long been used for the treatment of sepsis. In this investigation, by leaving one herb out each time, the four component herbs of HLJDD were reformulated to four HLJDD variants Form1-4, corresponding to the removal of Phellodendri Chinensis Cortex, Scutellariae Radix, Gardeniae Fructu and Coptidis Rhizoma, respectively. Metabolomics approach combined with histological inspection, biochemical measurement and molecular biology was used to investigate the treatment effects of HLJDD and its four variants on cecal ligation and puncture (CLP) model of sepsis, which were compared to decipher the formulating principles of HLJDD. Our results showed that HLJDD exhibit the strongest therapeutic effects in the CLP models as compared with the four variants, which could be ascribed to its most significant enhancement of cholinergic anti-inflammatory pathway and inhibition of HMGB-1/TLR4/NF-κB signaling pathway. Most of all, metabolites changed specifically between groups of HLJDD and its four variants were related with the exceptional treatment effects of HLJDD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Sepsis, severe sepsis and septic shock are the main cause of mortality in non-cardiac intensive care units. Immunometabolism has been linked to sepsis; however, the precise mechanism by which metabolic reprogramming regulates the inflammatory response is unclear. Here we show that aerobic glycolysis contributes to sepsis by modulating inflammasome activation in macrophages. PKM2-mediated glycolysis promotes inflammasome activation by modulating EIF2AK2 phosphorylation in macrophages. Pharmacological and genetic inhibition of PKM2 or EIF2AK2 attenuates NLRP3 and AIM2 inflammasomes activation, and consequently suppresses the release of IL-1β, IL-18 and HMGB1 by macrophages. Pharmacological inhibition of the PKM2-EIF2AK2 pathway protects mice from lethal endotoxemia and polymicrobial sepsis. Moreover, conditional knockout of PKM2 in myeloid cells protects mice from septic death induced by NLRP3 and AIM2 inflammasome activation. These findings define an important role of PKM2 in immunometabolism and guide future development of therapeutic strategies to treat sepsis., Competing Interests: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Increasing evidence suggests the important role of metabolic reprogramming in the regulation of the innate inflammatory response, but the underlying mechanism remains unclear. Here we provide evidence to support a novel role for the pyruvate kinase M2 (PKM2)-mediated Warburg effect, namely aerobic glycolysis, in the regulation of high-mobility group box 1 (HMGB1) release. PKM2 interacts with hypoxia-inducible factor 1α (HIF1α) and activates the HIF-1α-dependent transcription of enzymes necessary for aerobic glycolysis in macrophages. Knockdown of PKM2, HIF1α and glycolysis-related genes uniformly decreases lactate production and HMGB1 release. Similarly, a potential PKM2 inhibitor, shikonin, reduces serum lactate and HMGB1 levels, and protects mice from lethal endotoxemia and sepsis. Collectively, these findings shed light on a novel mechanism for metabolic control of inflammation by regulating HMGB1 release and highlight the importance of targeting aerobic glycolysis in the treatment of sepsis and other inflammatory diseases.

Sepsis is caused by an overwhelming immune response to bacterial infection. The discovery of high mobility group box 1 (HMGB1) as a late mediator of lethal sepsis has prompted investigation into the development of new therapeutics which specifically target this protein. Here, we show that chloroquine, an anti-malarial drug, prevents lethality in mice with established endotoxemia or sepsis. This effect is still observed even if administration of chloroquine is delayed. The protective effects of chloroquine were mediated through inhibition of HMGB1 release in macrophages, monocytes, and endothelial cells, thereby preventing its cytokine-like activities. As an inhibitor of autophagy, chloroquine specifically inhibited HMGB1-induced Iκ-B degradation and NF-κB activation. These findings define a novel mechanism for the anti-inflammatory effects of chloroquine and also suggest a new potential clinical use for this drug in the setting of sepsis., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Severe sepsis and septic shock are common and lethal conditions characterized by a systemic inflammatory response that is activated by invasive infection. In this study, a lipopolysaccharide (LPS) induced sepsis mice model was established to investigate the toxicities of LPS and the therapeutic effect of baicalin. Sera for clinical biochemistry and NMR metabolomic investigation, and liver and kidney tissues for histopathological examination, molecular biology measurement and NMR metabolomic profiling were collected. Multivariate analysis of metabolic profiles of the serum, liver and kidney extracts of mice revealed the occurrence of a severe inflammatory response, oxidative stress, and perturbances in energy and amino acid metabolism in LPS induced sepsis mice, which could be greatly ameliorated by baicalin treatment. This integrated 1H NMR based metabolomics approach gave us a new insight into the pathology of LPS induced sepsis, and helped in understanding the therapeutic effects of baicalin in a holistic view. [ABSTRACT FROM AUTHOR]