AKT/PKB Signaling: Navigating the Network

Cell, Journal Year: 2017, Volume and Issue: 169(3), P. 381 - 405

Published: April 1, 2017

Language: Английский

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Akt Signaling Pathway in Macrophage Activation and M1/M2 Polarization

The Journal of Immunology, Journal Year: 2017, Volume and Issue: 198(3), P. 1006 - 1014

Published: Jan. 23, 2017

Abstract Macrophages become activated initiating innate immune responses. Depending on the signals, macrophages obtain an array of activation phenotypes, described by broad terms M1 or M2 phenotype. The PI3K/Akt/mTOR pathway mediates signals from multiple receptors including insulin receptors, pathogen-associated molecular pattern cytokine adipokine and hormones. As a result, Akt converges inflammatory metabolic to regulate macrophage responses modulating their is family three serine-threonine kinases, Akt1, Akt2, Akt3. Generation mice lacking individual Akt, PI3K, mTOR isoforms utilization RNA interference technology have revealed that signaling components distinct isoform-specific roles in biology disease regulation, controlling cytokines, miRNAs, functions phagocytosis, autophagy, cell metabolism. Herein, we review current knowledge role macrophages, focusing M1/M2 polarization highlighting isoform–specific functions.

Language: Английский

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Regulation of innate immune cell function by mTOR

Nature reviews. Immunology, Journal Year: 2015, Volume and Issue: 15(10), P. 599 - 614

Published: Sept. 25, 2015

Language: Английский

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The Macrophage Switch in Obesity Development

Frontiers in Immunology, Journal Year: 2016, Volume and Issue: 6

Published: Jan. 5, 2016

Immune cell infiltration in (white) adipose tissue (AT) during obesity is associated with the development of insulin resistance. In AT, main population leukocytes are macrophages. Macrophages can be classified into two major populations: M1, classically activated macrophages, and M2, alternatively although recent studies have identified a broad range macrophage subsets. During obesity, AT M1 numbers increase correlate inflammation Upon activation, pro-inflammatory macrophages induce aerobic glycolysis. By contrast, lean humans mice, number M2 predominates. secrete anti-inflammatory cytokines utilize oxidative metabolism to maintain homeostasis. Here, we review immunologic metabolic functions their different facets syndrome.

Language: Английский

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Macrophage Metabolism Controls Tumor Blood Vessel Morphogenesis and Metastasis

Cell Metabolism, Journal Year: 2016, Volume and Issue: 24(5), P. 701 - 715

Published: Oct. 20, 2016

Language: Английский

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Macrophages regulate the progression of osteoarthritis

Osteoarthritis and Cartilage, Journal Year: 2020, Volume and Issue: 28(5), P. 555 - 561

Published: Jan. 23, 2020

OA is now well accepted as a low-grade inflammatory disease affecting the whole joint. In addition to mechanical loading, inflammation (particularly synovitis), contributes significantly OA. Synovial macrophages act immune cells and are of critical importance in symptomology structural progression Activated regulated by mTOR, NF-κB, JNK, PI3K/Akt other signaling pathways, polarized into either M1 or M2 subtypes synovial tissues, fluid, peripheral blood. The activation state M1/M2 ratio highly associated with severity. Aside from autocrine interactions, paracrine interactions between chondrocytes play vital role initiation development secreting cytokines, growth factors, matrix metalloproteinases (MMPs) tissue inhibitor (TIMPs), which lead subsequent cartilage degradation destruction. Treatments targeting relieve pain, protect synovitis, damage, osteophyte formation during development. Macrophage reprogramming transformation subtype, more than decrease quantity activated macrophages, appears be an effective treatment option for This review provides broad understanding contributions joint health disease. Multifunctional agents immunomodulatory effects on macrophage can skew microenvironment towards pro-chondrogenic atmosphere, thus, potential therapeutic options diseases.

Language: Английский

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Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation

eLife, Journal Year: 2016, Volume and Issue: 5

Published: Feb. 19, 2016

Macrophage activation/polarization to distinct functional states is critically supported by metabolic shifts. How polarizing signals coordinate and reprogramming, the potential implications for control of macrophage activation, remains poorly understood. Here we show that IL-4 signaling co-opts Akt-mTORC1 pathway regulate Acly, a key enzyme in Ac-CoA synthesis, leading increased histone acetylation M2 gene induction. Only subset genes controlled this way, including those regulating cellular proliferation chemokine production. Moreover, impinge on axis such activation. We propose calibrates state energetically demanding aspects which may define new role metabolism supporting

Language: Английский

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Increased miR‐124‐3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowthviatheir transfer into neurons

The FASEB Journal, Journal Year: 2017, Volume and Issue: 32(1), P. 512 - 528

Published: Sept. 21, 2017

Neuronal inflammation is the characteristic pathologic change of acute neurologic impairment and chronic traumatic encephalopathy after brain injury (TBI). Inhibiting excessive inflammatory response essential for improving outcome. To clarify regulatory mechanism microglial exosomes on neu-ronal in TBI, we focused studying impact exosomal miRNAs injured neurons this research. We used a repetitive (r)TBI mouse model harvested extracts from to phase TBI treat cultured BV2 microglia vitro. The were collected miRNA microarray analysis, which showed that expression level miR-124-3p increased most apparently miRNAs. found promoted anti-inflamed M2 polarization microglia, inhibited neuronal scratch-injured neurons. Further, mammalian target rapamycin (mTOR) signaling was implicated as being involved regulation by Gene Ontology Kyoto Encyclopedia Genes Genomes pathway analyses. Using mTOR activator MHY1485 confirmed inhibitory effect exerted suppressing activity signaling. PDE4B predicted be gene analysis. proved it directly targeted with luciferase reporter assay. overexpressed lentivirus transfection system, suggested suppressed mainly through inhibiting PDE4B. In addition, neurite outgrowth scratch injury, characterized an increase number branches total length, decreasedexpressiononRhoAand neurodegenerative proteins [Aß-peptide p-Tau]. It also improved outcome neuro-inflammation mice rTBI. Taken together, can inhibit contribute via their transfer into these effects targeting PDE4B, thus Therefore, could promising therapeutic interventions TBI. manipulated may provide novel therapy other diseases.—Huang, S., Ge, X., Yu, J., Han, Z., Yin, Li, Y., Chen, F., Wang, H., Zhang, Lei, P. Increased following inhibits contributes FASEB J. 32, 512-528 (2018). www.fasebj.org

Language: Английский

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mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation

Journal of Clinical Investigation, Journal Year: 2015, Volume and Issue: 125(5), P. 2090 - 2108

Published: April 19, 2015

Activation of mTOR-dependent pathways regulates the specification and differentiation CD4+ T effector cell subsets. Herein, we show that mTOR complex 1 (mTORC1) mTORC2 have distinct roles in generation CD8+ memory populations. Evaluation mice with a cell-specific deletion gene encoding negative regulator mTORC1, tuberous sclerosis 2 (TSC2), resulted highly glycolytic potent cells; however, due to constitutive mTORC1 activation, these cells retained terminally differentiated phenotype were incapable transitioning into state. In contrast, deficient activity loss RAS homolog enriched brain (RHEB) failed differentiate but characteristics, such as surface marker expression, lower metabolic rate, increased longevity. However, RHEB-deficient memory-like generate recall responses result defects. While influenced responses, regulated memory. inhibition reprogramming, which enhanced cells. Overall, results define specific for link metabolism suggest functions potential be targeted enhancing vaccine efficacy antitumor immunity.

Language: Английский

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Cellular Metabolism and Macrophage Functional Polarization

International Reviews of Immunology, Journal Year: 2014, Volume and Issue: 34(1), P. 82 - 100

Published: Oct. 23, 2014

Macrophages are a functionally heterogeneous cell population that is mainly shaped by variety of microenvironmental stimuli. Interferon γ (IFN-γ), interleukin-1β (IL-1β), and lipopolysaccharide (LPS) induce classical activation macrophages (M1), whereas IL-4 IL-13 an alternative program in (M2). Reprogramming intracellular metabolisms required for the proper polarization functions activated macrophages. Similar to Warburg effect observed tumor cells, M1 increase glucose consumption lactate release decreased oxygen rate. In comparison, M2 employ oxidative metabolism pathways. addition, fatty acids, vitamins, iron also related macrophage polarization. However, detailed metabolic pathways involved have remained elusive. Understanding bidirectional interactions between cellular physiological pathological situations regulatory may offer novel therapies macrophage-associated diseases.

Language: Английский

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