Immunometabolism最新文献

Background: A major contributor to cardiometabolic disease is caloric excess, often a result of consuming low cost, high calorie fast food. Studies have demonstrated the pivotal role of gut microbes contributing to cardiovascular disease in a diet-dependent manner. Given the central contributions of diet and gut microbiota to cardiometabolic disease, we hypothesized that microbial metabolites originating after fast food consumption can elicit acute metabolic responses in the liver.

Methods: We gave conventionally raised mice or mice that had their microbiomes depleted with antibiotics a single oral gavage of a liquified fast food meal or liquified control rodent chow meal. After four hours, mice were sacrificed and we used untargeted metabolomics of portal and peripheral blood, 16S rRNA gene sequencing, targeted liver metabolomics, and host liver RNA sequencing to identify novel fast food-derived microbial metabolites and their acute effects on liver function.

Results: Several candidate microbial metabolites were enriched in portal blood upon fast food feeding, and were essentially absent in antibiotic-treated mice. Strikingly, at four hours post-gavage, fast food consumption resulted in rapid reorganization of the gut microbial community and drastically altered hepatic gene expression. Importantly, diet-driven reshaping of the microbiome and liver transcriptome was dependent on an intact microbial community and not observed in antibiotic ablated animals.

Conclusions: Collectively, these data suggest a single fast food meal is sufficient to reshape the gut microbial community in mice, yielding a unique signature of food-derived microbial metabolites. Future studies are in progress to determine the contribution of select metabolites to cardiometabolic disease progression and the translational relevance of these animal studies.

Fundamental modulation of energy metabolism in immune cells is increasingly being recognized for the ability to impart important changes in cellular properties. In homeostasis, cells of the innate immune system, such as monocytes, macrophages and dendritic cells (DCs), are enabled to respond rapidly to various forms of acute cellular and environmental stress, such as pathogens. In chronic stress milieus, these cells may undergo a re-programming, thereby triggering processes that may instigate tissue damage and failure of resolution. In settings of metabolic dysfunction, moieties such as excess sugars (glucose, fructose and sucrose) accumulate in the tissues and may form advanced glycation end products (AGEs), which are signaling ligands for the receptor for advanced glycation end products (RAGE). In addition, cellular accumulation of cholesterol species such as that occurring upon macrophage engulfment of dead/dying cells, presents these cells with a major challenge to metabolize/efflux excess cholesterol. RAGE contributes to reduced expression and activities of molecules mediating cholesterol efflux. This Review chronicles examples of the roles that sugars and cholesterol, via RAGE, play in immune cells in instigation of maladaptive cellular signaling and the mediation of chronic cellular stress. At this time, emerging roles for the ligand-RAGE axis in metabolism-mediated modulation of inflammatory signaling in immune cells are being unearthed and add to the growing body of factors underlying pathological immunometabolism.

In this commentary we discuss new findings presented by Shang et al. regarding the role of macrophage-derived glutamine in skeletal muscle repair. Loss-of-function of glutamate dehydrogenase in macrophages led to an upregulation of glutamine synthesis which sustained glutamine levels in muscle tissue and facilitated satellite cell proliferation and differentiation.

Targeting glycolysis in T helper 17 (Th17) cells presents an attractive opportunity to treat Th17 cell-mediated autoimmune diseases such as multiple sclerosis (MS). Pyruvate kinase isoform 2 (PKM2) is a glycolytic enzyme expressed in T cells infiltrating the central nervous system in a mouse model of MS, suggesting PKM2 modulation could provide a new avenue for MS therapeutics. In a recent article in Science Signaling, Seki et al. show that pharmacological modulation of PKM2 alters but does not ameliorate disease in a mouse model of MS. These results warrant further consideration of PKM2 modulators to treat Th17 cell-mediated autoimmunity.

Macrophages are instrumental for the repair of organs that become injured due to ischemia, yet their potential for healing is sensitive to the availability of metabolites from the surrounding milieu. This sensitivity extends beyond anabolic and catabolic reactions, as metabolites are also leveraged to control production of secreted factors that direct intercellular crosstalk. In response to limiting extracellular oxygen, acute-phase macrophages activate hypoxia-inducible transcription factors that repurpose cellular metabolism. Subsequent repair-phase macrophages secrete cytokines to activate stromal cells, the latter which contribute to matrix deposition and scarring. As we now appreciate, these distinct functions are calibrated by directing flux of carbons and cofactors into specific metabolic shunts. This occurs through glycolysis, the pentose phosphate shunt, the tricarboxylic acid cycle, oxidative phosphorylation, nicotinamide adenine dinucleotides, lipids, amino acids, and through lesser understood pathways. The integration of metabolism with macrophage function is particularly important during injury to the ischemic heart, as glucose and lipid imbalance lead to inefficient repair and permanent loss of non-regenerative muscle. Here we review macrophage metabolic signaling under ischemic stress with implications for cardiac repair.

Immune reconstitution following allogeneic hematopoietic stem cell transplantation (allo-HSCT) sets the stage for the goal of a successful transplant-the prevention of disease relapse without graft versus host disease (GVHD) and opportunistic infection. In both epidemiologic studies and in controlled animal studies, it is known that the gut microbiome (GM) can profoundly influence normal innate and adaptive immune development and can be altered by microbial transfer and antibiotics. Following allo-HSCT the GM has been shown to influence clinical outcomes but published associations between the GM and immune reconstitution post-allo-HSCT are lacking. In this viewpoint we propose that the extensive knowledge garnered from studying normal immune development can serve as a framework for studying immune development post-allo-HSCT. We summarize existing studies addressing the effect of the GM on immune ontogeny and draw associations with immune reconstitution and the GM post-allo-HSCT.

Akt kinases translate various external cues into intracellular signals that control cell survival, proliferation, metabolism and differentiation. This review discusses the requirement for Akt and its targets in determining the fate and function of T cells. We discuss the importance of Akt at various stages of T cell development including β-selection during which Akt fulfills the energy requirements of highly proliferative DN3 cells. Akt also plays an integral role in CD8 T cell biology where its regulation of Foxo transcription factors and mTORC1 metabolic activity controls effector versus memory CD8 T cell differentiation. Finally, Akt promotes the differentiation of naïve CD4 T cells into Th1, Th17 and Tfh cells but inhibits the development of Treg cells. We also highlight how modulating Akt in T cells is a promising avenue for enhancing cell-based cancer immunotherapy.

Adipose tissue inflammation continues to represent a significant area of research in immunometabolism. We have identified a transcription factor, EBF1, which crucially regulates the expression of numerous inflammatory loci in adipocytes. However, EBF1 appears to do so without physically binding to these inflammatory genes. Our research is currently focused on understanding this discrepancy, and we believe that future findings could pave the road for drug development aimed to block adipose inflammation at its source.

We review here the seminal findings of Desdin-Mico et al. showing that T cells with dysfunctional mitochondria induce multimorbity and premature senescence, due to mitochondrial transcription factor A (TFAM). They add further weight to the idea that targeting immunometabolism could be beneficial in combating the detrimental effects of age-related disease.

Assays to monitor the metabolic state or nutrient uptake capacity of immune cells at a single cell level are increasingly in demand. One assay, used by many immunologists, employs 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG), a fluorescent analogue of 2-deoxyglucose (2DG), as a substrate for glucose transporters. This molecule has been validated as a substrate for the glucose transporter Glut2 (Slc2a2) in mammalian cells but 2-NDBG selectivity for the glucose transporters expressed by T cells, Glut1 (Slc2a1) and Glut3 (Slc2a3), has never been explored. Nor has the possibility that 2-NBDG might bind to T cells that do not express glucose transporters been assessed. In this technical commentary we interrogate the specificity of 2-NBBG labelling as a readout for glucose transport in T lymphocytes. We compare flow cytometric 2-NBDG staining against well validated radiolabelled glucose transport assays in murine T cells. Our data show there can be a large discordance between glucose transport capacity and 2-NBDG labelling in T cells. We also find that 2-NBDG uptake into murine T cells is not inhibited by competitive substrates or facilitative glucose transporter inhibitors, nor can 2-NBDG competitively block glucose uptake in T cells. Collectively, these data argue that 2-NBDG uptake alone is not a reliable tool for the assessment of cellular glucose transport capacity.