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Immune cell metabolism is dynamically regulated in parallel with the substantial changes in cellular function that accompany immune cell activation. While these changes in metabolism are important for facilitating the increased energetic and biosynthetic demands of activated cells, immune cell metabolism also has direct roles in controlling the functions of immune cells and shaping the immune response. A theme is emerging wherein nutrients, metabolic enzymes, and metabolites can act as an extension of the established immune signal transduction pathways, thereby adding an extra layer of complexity to the regulation of immunity. This Review will outline the metabolic configurations adopted by different immune cell subsets, describe the emerging roles for metabolic enzymes and metabolites in the control of immune cell function, and discuss the therapeutic implications of this emerging immune regulatory axis.

Natural killer (NK) cells are lymphocytes with important anti-tumour functions. Cytokine activation of NK cell glycolysis and oxidative phosphorylation (OXPHOS) are essential for robust NK cell responses. However, the mechanisms leading to this metabolic phenotype are unclear. Here we show that the transcription factor cMyc is essential for IL-2/IL-12-induced metabolic and functional responses in mice. cMyc protein levels are acutely regulated by amino acids; cMyc protein is lost rapidly when glutamine is withdrawn or when system l -amino acid transport is blocked. We identify SLC7A5 as the predominant system l -amino acid transporter in activated NK cells. Unlike other lymphocyte subsets, glutaminolysis and the tricarboxylic acid cycle do not sustain OXPHOS in activated NK cells. Glutamine withdrawal, but not the inhibition of glutaminolysis, results in the loss of cMyc protein, reduced cell growth and impaired NK cell responses. These data identify an essential role for amino acid-controlled cMyc for NK cell metabolism and function. Glutamine can feed into the TCA cycle as a fuel for oxidative phosphorylation and thereby can affect metabolic pathways in lymphocytes. Yet here the authors show that glutamine serves predominantly as a signalling molecule that sustains cMyc expression to control NK cell metabolism and effector function.

NK cells are cytotoxic cells that combat tumors and viral infection. Finlay and colleagues show that the effector function of cytokine-activated NK cells depends on glucose metabolism via the citrate–malate shuttle that requires the metabolic regulator Srebp. Activated natural killer (NK) cells engage in a robust metabolic response that is required for normal effector function. Using genetic, pharmacological and metabolic analyses, we demonstrated an essential role for Srebp transcription factors in cytokine-induced metabolic reprogramming of NK cells that was independent of their conventional role in the control of lipid synthesis. Srebp was required for elevated glycolysis and oxidative phosphorylation and promoted a distinct metabolic pathway configuration in which glucose was metabolized to cytosolic citrate via the citrate–malate shuttle. Preventing the activation of Srebp or direct inhibition of the citrate–malate shuttle inhibited production of interferon-γ and NK cell cytotoxicity. Thus, Srebp controls glucose metabolism in NK cells, and this Srebp-dependent regulation is critical for NK cell effector function.

Mitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1β in vitro. Accordingly, HIF-1α and IL-1β are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2 −/− mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell. IL-10 can limit inflammation in part by inhibiting miR-155. Here the authors show how this axis induces mitochondrial arginase-2 to alter the mitochondrial dynamics and bioenergetics of macrophages and make these cells less pro-inflammatory.

In this trial, 3445 patients with heart failure and a preserved ejection fraction were assigned to spironolactone or placebo. At a mean of 3.3 years, there was no significant difference in death from cardiovascular causes, aborted cardiac arrest, or hospitalization for heart failure. Many patients with heart failure have a normal or near-normal left ventricular ejection fraction. 1 – 4 Such patients share common signs and symptoms, as well as an impaired quality of life and a poor prognosis, with patients who have heart failure and a reduced ejection fraction. 5 – 8 However, the benefit of most medical therapies for heart failure is limited to those with a reduced ejection fraction, generally 40% or less. 1 , 2 , 9 The lack of favorable evidence from clinical-outcome trials involving patients with heart failure and a preserved left ventricular ejection fraction is reflected in current guidelines, which offer no specific . . .

Mass loss from the Antarctic Ice Sheet to the ocean has increased in recent decades, largely because the thinning of its floating ice shelves has allowed the outflow of grounded ice to accelerate 1 , 2 . Enhanced basal melting of the ice shelves is thought to be the ultimate driver of change 2 , 3 , motivating a recent focus on the processes that control ocean heat transport onto and across the seabed of the Antarctic continental shelf towards the ice 4 – 6 . However, the shoreward heat flux typically far exceeds that required to match observed melt rates 2 , 7 , 8 , suggesting that other critical controls exist. Here we show that the depth-independent (barotropic) component of the heat flow towards an ice shelf is blocked by the marked step shape of the ice front, and that only the depth-varying (baroclinic) component, which is typically much smaller, can enter the sub-ice cavity. Our results arise from direct observations of the Getz Ice Shelf system and laboratory experiments on a rotating platform. A similar blocking of the barotropic component may occur in other areas with comparable ice–bathymetry configurations, which may explain why changes in the density structure of the water column have been found to be a better indicator of basal melt rate variability than the heat transported onto the continental shelf 9 . Representing the step topography of the ice front accurately in models is thus important for simulating ocean heat fluxes and induced melt rates. The front of the Getz Ice Shelf in West Antarctica creates an abrupt topographic step that deflects ocean currents, suppressing 70% of the heat delivery to the ice sheet.

Despite increasing prevalence of heart failure (HF) in patients with preserved ejection fraction (PEF), there are no available therapies proven to reduce morbidity and mortality. Aldosterone, a potent stimulator of myocardial and vascular fibrosis, may be a key mediator of HF progression in this population and is therefore an important therapeutic target. The TOPCAT trial is designed to evaluate the effect of spironolactone, an aldosterone antagonist, on morbidity, mortality, and quality of life in patients with HF-PEF. Up to 3,515 patients with HF-PEF will be randomized in double-blind fashion to treatment with spironolactone (target dose 30 mg daily) or matching placebo. Eligible patients include those with age ≥50 years, left ventricular ejection fraction ≥45%, symptomatic HF, and either a hospitalization for HF within the prior year or an elevated natriuretic peptide level (B-type natriuretic peptide ≥100 pg/mL or N-terminal pro–B-type natriuretic peptide ≥360 pg/mL) within the 60 days before randomization. Patients with uncontrolled hypertension and those with known infiltrative or hypertrophic cardiomyopathy are excluded. The primary end point is the composite of cardiovascular death, hospitalization for HF, or aborted cardiac arrest. Key secondary end points include quality of life, nonfatal cardiovascular events, and new-onset atrial fibrillation. Ancillary studies of echocardiography, tonometry, and cardiac biomarkers will provide more insight regarding this understudied population and the effects of spironolactone therapy. TOPCAT is designed to assess definitively the role of spironolactone in the management of HF-PEF.

Idealised and hindcast simulations performed with the stand-alone ocean carbon-cycle configuration of the Norwegian Earth System Model (NorESM-OC) are described and evaluated. We present simulation results of three different model configurations (two different model versions at different grid resolutions) using two different atmospheric forcing data sets. Model version NorESM-OC1 corresponds to the version that is included in the NorESM-ME1 fully coupled model, which participated in CMIP5. The main update between NorESM-OC1 and NorESM-OC1.2 is the addition of two new options for the treatment of sinking particles. We find that using a constant sinking speed, which has been the standard in NorESM's ocean carbon cycle module HAMOCC (HAMburg Ocean Carbon Cycle model), does not transport enough particulate organic carbon (POC) into the deep ocean below approximately 2000 m depth. The two newly implemented parameterisations, a particle aggregation scheme with prognostic sinking speed, and a simpler scheme that uses a linear increase in the sinking speed with depth, provide better agreement with observed POC fluxes. Additionally, reduced deep ocean biases of oxygen and remineralised phosphate indicate a better performance of the new parameterisations. For model version 1.2, a re-tuning of the ecosystem parameterisation has been performed, which (i) reduces previously too high primary production at high latitudes, (ii) consequently improves model results for surface nutrients, and (iii) reduces alkalinity and dissolved inorganic carbon biases at low latitudes. We use hindcast simulations with prescribed observed and constant (pre-industrial) atmospheric CO2 concentrations to derive the past and contemporary ocean carbon sink. For the period 1990-1999 we find an average ocean carbon uptake ranging from 2.01 to 2.58 Pg C yr1 depending on model version, grid resolution, and atmospheric forcing data set.

The activated leukocyte cell adhesion molecule (ALCAM) is overexpressed in many mammary tumors, but controversial results about its role and prognostic impact in breast cancer have been reported. Therefore, we evaluated the biologic effects of ALCAM expression in two breast cancer cell lines and a larger cohort of mammary carcinomas. By stable transfections, MCF7 cells with ALCAM overexpression and MDA-MB231 cells with reduced ALCAM levels were generated and analyzed in functional assays and cDNA microarrays. In addition, an immunohistochemical study on 347 patients with breast cancer with long-term follow-up and analysis of disseminated tumor cells (DTCs) was performed. In both cell lines, high ALCAM expression was associated with reduced cell motility. In addition, ALCAM silencing in MDA-MB231 cells resulted in lower invasive potential, whereas high ALCAM expression was associated with increased apoptosis in both cell lines. Among genes which were differentially expressed in clones with altered ALCAM expression, there was an overlap of 15 genes between both cell lines, among them cathepsin D, keratin 7, gelsolin, and ets2 whose deregulation was validated by western blot analysis. In MDA-MB231 cells, we observed a correlation with VEGF expression which was validated by enzyme-linked immuno sorbent assay (ELISA). Our IHC results on primary breast carcinomas showed that ALCAM expression was associated with an estrogen receptor-positive phenotype. In addition, strong ALCAM immunostaining correlated with nodal involvement and the presence of tumor cells in bone marrow. By Kaplan–Meier analysis, strong ALCAM expression in ductal carcinomas correlated with shorter recurrence-free intervals ( P  = 0.048) and overall survival (OAS, P  = 0.003). Our results indicate that the biologic role of ALCAM in breast cancer is complex, but overexpression might be relevant for outcome in ductal carcinomas.