Background: Nuclear SIRT1 and SIRT6 switch monocyte energy sources from glycolysis to fatty acid oxidation during sepsis adaptation. Results: Sequential actions of nuclear SIRT1 and RELB differentially induce SIRT3 expression and increase mitochondrial biogenesis during sepsis adaptation. Conclusion: SIRT1 and RELB link nuclear and mitochondrial alterations in bioenergetics during sepsis. Significance: Communication between nuclear and mitochondrial functions may influence sepsis outcomes.

We review the emerging concept that changes in cellular bioenergetics concomitantly reprogram inflammatory and metabolic responses. The molecular pathways of this integrative process modify innate and adaptive immune reactions associated with inflammation, as well as influencing the physiology of adjacent tissue and organs. The initiating proinflammatory phase of inflammation is anabolic and requires glucose as the primary fuel, whereas the opposing adaptation phase is catabolic and requires fatty acid oxidation. The fuel switch to fatty acid oxidation depends on the sensing of AMP and NAD(+) by AMPK and the SirT family of deacetylases (e.g., SirT1, -6, and -3), respectively, which couple inflammation and metabolism by chromatin and protein reprogramming. The AMP-AMPK/NAD(+)-SirT axis proceeds sequentially during acute systemic inflammation associated with sepsis but ceases during chronic inflammation associated with diabetes, obesity, and atherosclerosis. Rebalancing bioenergetics resolves inflammation. Manipulating cellular bioenergetics is identifying new ways to treat inflammatory and immune diseases.

Expression of the inflammatory cytokine TNF is tightly controlled. During endotoxin tolerance, transcription of TNF mRNA is repressed, although not entirely eliminated. Production of TNF cytokine, however, is further controlled by post-transcriptional regulation. In this study, we detail a mechanism of post-transcriptional repression of TNF mRNA by GAPDH binding to the TNF 3’UTR. Using RNA immunoprecipitation, we demonstrate that GAPDH-TNF mRNA binding increases when THP-1 monocytes are in a low glycolysis state, and that this binding can be reversed by knocking down GAPDH expression or by increasing glycolysis. We show that reducing glycolysis decreases TNF mRNA association with polysomes. We demonstrate that GAPDH-TNF mRNA binding results in post-transcriptional repression of TNF and that the TNF mRNA 3’UTR is sufficient for repression. Finally, after exploring this model in THP-1 cells, we demonstrate this mechanism affects TNF expression in primary human monocytes and macrophages. We conclude that GAPDH-TNF mRNA binding regulates expression of TNF based on cellular metabolic state. We believe this mechanism has potentially significant implications for treatment of various immunometabolic conditions, including immune paralysis during septic shock.

RelB is one of the more unusual members of the NF-κB family. This family, arguably the best known group of transcription regulators, regulates an astonishing array of cell types and biological processes. This includes regulation of cell growth, differentiation and death by apoptosis, and the development and function of the innate and adaptive-immune system. RelB is best known for its roles in lymphoid development, DC biology, and noncanonical signaling. Within the last few years, however, surprising functions of RelB have emerged. The N-terminal leucine zipper motif of RelB, a motif unique among the NF-κB family, may associate with more diverse DNA sequences than other NF-κB members. RelB is capable of direct binding to the AhR that supports the xenobiotic-detoxifying pathway. RelB can regulate the circadian rhythm by directly binding to the BMAL partner of CLOCK. Finally, RelB also couples with bioenergy NAD(+) sensor SIRT1 to integrate acute inflammation with changes in metabolism and mitochondrial bioenergetics. In this review, we will explore these unique aspects of RelB, specifically with regard to its role in immunity.

SUMMARYWe studied changes in species distribution and antimicrobial resistance patterns of Shigella during 1980-2008, using the Diarrhoeal Diseases Surveillance system of Dhaka Hospital of ICDDR,B. In hospitalized patients Shigella prevalence decreased steadily from 8-12 % in the 1980s to 3% in 2008. Endemic S. flexneri was the most commonly isolated species (54 %). Epidemic S. dysenteriae type 1 had two peaks in 1984 and 1993, but was not found after 2000, except for one case in 2004. The therapeutic options are now limited : in 2008 a total of 33 % of S. flexneri were resistant to ciprofloxacin and 57 % to mecillinam. In the <5 years age group, severely underweight, wasted and stunted children were more at risk of shigellosis compared to well-nourished children (P<0 . 001). Although hospitalization for Shigella diarrhoea is decreasing, the high levels of antimicrobial resistance and increased susceptibility of malnourished children continue to pose an ongoing risk.