AKT mediated glycolytic shift regulates autophagy in classically activated macrophages.
01 Sep 2015-The International Journal of Biochemistry & Cell Biology (Int J Biochem Cell Biol)-Vol. 66, pp 121-133
TL;DR: A novel link between AKT mediated glycolytic metabolism and autophagy in the activated macrophages is reported to provide a possible mechanism for sustained macrophage activation in vivo.
About: This article is published in The International Journal of Biochemistry & Cell Biology.The article was published on 2015-09-01. It has received 23 citations till now. The article focuses on the topics: Programmed cell death & Autophagy.
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TL;DR: The current knowledge on the role of the Akt signaling pathway in macrophages is reviewed, focusing on M1/M2 polarization and highlighting Akt isoform–specific functions.
Abstract: Macrophages become activated initiating innate immune responses. Depending on the signals, macrophages obtain an array of activation phenotypes, described by the broad terms of M1 or M2 phenotype. The PI3K/Akt/mTOR pathway mediates signals from multiple receptors including insulin receptors, pathogen-associated molecular pattern receptors, cytokine receptors, adipokine receptors, and hormones. As a result, the Akt pathway converges inflammatory and metabolic signals to regulate macrophage responses modulating their activation phenotype. Akt is a family of three serine-threonine kinases, Akt1, Akt2, and Akt3. Generation of mice lacking individual Akt, PI3K, or mTOR isoforms and utilization of RNA interference technology have revealed that Akt signaling pathway components have distinct and isoform-specific roles in macrophage biology and inflammatory disease regulation, by controlling inflammatory cytokines, miRNAs, and functions including phagocytosis, autophagy, and cell metabolism. Herein, we review the current knowledge on the role of the Akt signaling pathway in macrophages, focusing on M1/M2 polarization and highlighting Akt isoform-specific functions.
585 citations
Cites background from "AKT mediated glycolytic shift regul..."
...Accordingly, M1 macrophages that have active glycolysis exhibit reduced autophagy (97)....
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TL;DR: The influence of autophagy on functional cellular responses, such as phagocytosis, antigen presentation, cytokine production, control of inflammasome activation, tolerance and the consequences for overall host defense are discussed.
Abstract: Autophagy is well equipped functionally to isolate microbial pathogens in autophagosomes and to carry out their clearance by dismemberment in the course of catabolic processes in the lysosome. Clearly, this is a non-metabolic function of autophagy that impacts strongly on the immune system. While in a preceding article on neutrophils, eosinophils, mast cells, and natural killer cells our focus was on the role of autophagy in regulating innate immune cell differentiation, degranulation, phagocytosis and extracellular trap formation, here we discuss monocytes/macrophages and dendritic cells, specifically, the influence of autophagy on functional cellular responses, such as phagocytosis, antigen presentation, cytokine production, control of inflammasome activation, tolerance and the consequences for overall host defense.
175 citations
TL;DR: The contrasting role of autophagy adaptors being both selective as well as pleotropic in functions is explored and whether E3 ligases could bring in the specificity to cargo selectivity is discussed.
Abstract: Autophagy, a cellular homeostatic process, which ensures cellular survival under various stress conditions, has catapulted to the forefront of innate defense mechanisms during intracellular infections. The ability of autophagy to tag and target intracellular pathogens towards lysosomal degradation is central to this key defense function. However, studies involving the role and regulation of autophagy during intracellular infections largely tend to ignore the housekeeping function of autophagy. A growing number of evidences now suggest that the housekeeping function of autophagy, rather than the direct pathogen degradation function, may play a decisive role to determine the outcome of infection and immunological balance. We discuss herein the studies that establish the homeostatic and anti-inflammatory function of autophagy, as well as role of bacterial effectors in modulating and coopting these functions. Given that the core autophagy machinery remains largely the same across diverse cargos, how selectivity plays out during intracellular infection remains intriguing. We explore here, the contrasting role of autophagy adaptors being both selective as well as pleotropic in functions and discuss whether E3 ligases could bring in the specificity to cargo selectivity.
169 citations
TL;DR: Results indicate that urolithin A treatment attenuates pro‐inflammatory mediator production by suppressing NOX‐derived reactive oxygen species‐mediated PI3‐K/Akt/NF‐&kgr;B and JNK/AP‐1 signaling pathways in LPS‐stimulated macrophages.
58 citations
Cites background from "AKT mediated glycolytic shift regul..."
...In contrast, activation of mTOR, which is elicited by Akt, has been revealed to block autophagy (Matta and Kumar, 2015; Pattingre et al., 2008)....
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TL;DR: The findings suggest that the metabolic state of target cells is an intrinsic host factor that determines the extent of norovirus replication and implicates glycolysis as a virulence determinant.
Abstract: The metabolic pathways of central carbon metabolism, glycolysis and oxidative phosphorylation (OXPHOS), are important host factors that determine the outcome of viral infections and can be manipulated by some viruses to favor infection. However, mechanisms of metabolic modulation and their effects on viral replication vary widely. Herein, we present the first metabolomics and energetic profiling of norovirus-infected cells, which revealed increases in glycolysis, OXPHOS, and the pentose phosphate pathway (PPP) during murine norovirus (MNV) infection. Inhibiting glycolysis with 2-deoxyglucose (2DG) in macrophages revealed that glycolysis is an important factor for optimal MNV infection, while inhibiting the PPP and OXPHOS showed a relatively minor impact of these pathways on MNV infection. 2DG affected an early stage in the viral life cycle after viral uptake and capsid uncoating, leading to decreased viral protein production and viral RNA. The requirement of glycolysis was specific for MNV (but not astrovirus) infection, independent of the type I interferon antiviral response, and unlikely to be due to a lack of host cell nucleotide synthesis. MNV infection increased activation of the protein kinase Akt, but not AMP-activated protein kinase (AMPK), two master regulators of cellular metabolism, implicating Akt signaling in upregulating host metabolism during norovirus infection. In conclusion, our findings suggest that the metabolic state of target cells is an intrinsic host factor that determines the extent of norovirus replication and implicates glycolysis as a virulence determinant. They further point to cellular metabolism as a novel therapeutic target for norovirus infections and improvements in current human norovirus culture systems.IMPORTANCE Viruses depend on the host cells they infect to provide the machinery and substrates for replication. Host cells are highly dynamic systems that can alter their intracellular environment and metabolic behavior, which may be helpful or inhibitory for an infecting virus. In this study, we show that macrophages, a target cell of murine norovirus (MNV), increase glycolysis upon viral infection, which is important for early steps in MNV infection. Human noroviruses (hNoV) are a major cause of gastroenteritis globally, causing enormous morbidity and economic burden. Currently, no effective antivirals or vaccines exist for hNoV, mainly due to the lack of high-efficiency in vitro culture models for their study. Thus, insights gained from the MNV model may reveal aspects of host cell metabolism that can be targeted for improving hNoV cell culture systems and for developing effective antiviral therapies.
55 citations
Cites background from "AKT mediated glycolytic shift regul..."
...Akt has been implicated in regulating reactive oxygen species (ROS) generation (75)....
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References
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TL;DR: The origins, challenges and solutions of NIH Image and ImageJ software are discussed, and how their history can serve to advise and inform other software projects.
Abstract: For the past 25 years NIH Image and ImageJ software have been pioneers as open tools for the analysis of scientific images. We discuss the origins, challenges and solutions of these two programs, and how their history can serve to advise and inform other software projects.
44,587 citations
TL;DR: It is shown that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome, and may explain the frequent association of mitochondrial damage with inflammatory diseases.
Abstract: An inflammatory response initiated by the NLRP3 inflammasome is triggered by a variety of situations of host 'danger', including infection and metabolic dysregulation. Previous studies suggested that NLRP3 inflammasome activity is negatively regulated by autophagy and positively regulated by reactive oxygen species (ROS) derived from an uncharacterized organelle. Here we show that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome. Resting NLRP3 localizes to endoplasmic reticulum structures, whereas on inflammasome activation both NLRP3 and its adaptor ASC redistribute to the perinuclear space where they co-localize with endoplasmic reticulum and mitochondria organelle clusters. Notably, both ROS generation and inflammasome activation are suppressed when mitochondrial activity is dysregulated by inhibition of the voltage-dependent anion channel. This indicates that NLRP3 inflammasome senses mitochondrial dysfunction and may explain the frequent association of mitochondrial damage with inflammatory diseases.
3,985 citations
"AKT mediated glycolytic shift regul..." refers background in this paper
...…ce pt ed M an us cr ip t 21 suggesting mitochondrial release of ROS that requires an active electron transport 466 through mitochondrial complex I. 467 Interestingly, depolarized mitochondria or damaged mitochondria are known to 468 activate inflammatory pathways in macrophages (Zhou et al., 2011)....
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...467 Interestingly, depolarized mitochondria or damaged mitochondria are known to 468 activate inflammatory pathways in macrophages (Zhou et al., 2011)....
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TL;DR: How cytokines and pathogen signals influence macrophages' functional phenotypes and the evidence for M1 and M2 functions is assessed and a paradigm initially based on the role of a restricted set of selected ligands in the immune response is revisited.
Abstract: Macrophages are endowed with a variety of receptors for lineage-determining growth factors, T helper (Th) cell cytokines, and B cell, host, and microbial products. In tissues, macrophages mature and are activated in a dynamic response to combinations of these stimuli to acquire specialized functional phenotypes. As for the lymphocyte system, a dichotomy has been proposed for macrophage activation: classic vs. alternative, also M1 and M2, respectively. In view of recent research about macrophage functions and the increasing number of immune-relevant ligands, a revision of the model is needed. Here, we assess how cytokines and pathogen signals influence their functional phenotypes and the evidence for M1 and M2 functions and revisit a paradigm initially based on the role of a restricted set of selected ligands in the immune response.
3,674 citations
"AKT mediated glycolytic shift regul..." refers background in this paper
...Macrophages 66 activated with both IFN-γ and LPS show synergistic phenotype and are defined as 67 classically activated macrophages or M1 macrophages (Martinez and Gordon, 2014)....
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TL;DR: Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria, meaning that mitochondria coordinate the late stage of cellular demise.
Abstract: Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.
3,340 citations
"AKT mediated glycolytic shift regul..." refers background in this paper
...7 cells 334 A decrease in MOMP or depolarization of mitochondria is known to activate the 335 inflammatory pathways that could eventually lead to cell death (Kroemer et al., 2007)....
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...IFNγ+LPS induced activation leads to cell death in Raw 264.7 cells 334 A decrease in MOMP or depolarization of mitochondria is known to activate the 335 inflammatory pathways that could eventually lead to cell death (Kroemer et al., 2007)....
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TL;DR: There appears to be at least three different populations of activated macrophages with three distinct biological functions, the most recent addition is the type 2-activated macrophage, which is anti-inflammatory and preferentially induces Th2-type humoral-immune responses to antigen.
Abstract: It used to be easy. In the old days ( 8 years ago), activated macrophages were simply defined as cells that secreted inflammatory mediators and killed intracellular pathogens. Things are becoming progressively more complicated in the world of leukocyte biology. Activated macrophages may be a more heterogenous group of cells than originally appreciated, with different physiologies and performing distinct immunological functions. The first hint of this heterogeneity came with the characterization of the “alternatively activated macrophage” [1]. The exposure of macrophages to interleukin (IL)-4 or glucocorticoids induced a population of cells that up-regulated certain phagocytic receptors but failed to produce nitrogen radicals [2] and as a result, were relatively poor at killing intracellular pathogens. Recent studies have shown that these alternatively activated cells produce several components involved in the synthesis of the extracellular matrix (ECM) [3], suggesting their primary role may be involved in tissue repair rather than microbial killing. It turns out that the name alternatively activated macrophage may be unfortunate for a few reasons. First, although these cells express some markers of activation, they have not been exposed to the classical, activating stimuli, interferon(IFN) and lipopolysaccharide (LPS). Second, and more importantly, the name implies that this is the only other way to activate a macrophage. Recent studies suggest that this may not be the case. Exposure of macrophages to classical activating signals in the presence of immunoglobulin G (IgG) immune complexes induced the production of a cell type that was fundamentally different from the classically activated macrophage. These cells generated large amounts of IL-10 and as a result, were potent inhibitors of acute inflammatory responses to bacterial endotoxin [4]. These activated macrophages have been called type 2-activated macrophages [5] because of their ability to induce T helper cell type 2 (Th2) responses that were predominated by IL-4 [6], leading to IgG class-switching by B cells. Thus, at this time, there appears to be at least three different populations of activated macrophages with three distinct biological functions. The first and most well described is the classically activated macrophage whose role is as an effector cell in Th1 cellular immune responses. The second type of cell, the alternatively activated macrophage, appears to be involved in immunosuppression and tissue repair. The most recent addition to this list is the type 2-activated macrophage, which is anti-inflammatory and preferentially induces Th2-type humoral-immune responses to antigen. Together, these three populations of cells may form their own regulatory network to prevent a well-intentioned immune response from progressing to immunopathology. THE CLASSICALLY ACTIVATED MACROPHAGE
1,903 citations
"AKT mediated glycolytic shift regul..." refers background or methods in this paper
...60 Stimulating macrophages with IFN-γ treatment primes them for enhanced innate 61 immune functions like higher phagocytosis, lysosomal acidification and oxidative 62 bursts (Mosser, 2003)....
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...83 Classical activation of macrophages by IFN-γ and LPS treatment results in increased 84 nitric oxide (NO) production, dramatically higher glycolytic rate and higher oxidative 85 potential (Totemeyer et al., 2006, Haschemi et al., 2012, Mosser, 2003)....
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...Activation induced Nitric oxide (NO) is required for autophagy inhibition 269 Classical activation is known to induce the expression of iNOS and thereby leads to 270 increased production of Nitric Oxide (Mosser, 2003)....
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...Nitric Oxide (NO) was measured using Nitrite Colorimetric Assay Kit 190 following the manufacturer‟s protocol (Cayman Chemical)....
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