Role of exosomal non-coding RNAs from tumor cells and tumor-associated macrophages in the tumor microenvironment DOI Creative Commons

Zijie Xu,

Yi Chen, Ling Ma

et al.

Molecular Therapy, Journal Year: 2022, Volume and Issue: 30(10), P. 3133 - 3154

Published: April 9, 2022

Exosomes have a crucial role in intercellular communication and mediate interactions between tumor cells tumor-associated macrophages (TAMs). Exosome-encapsulated non-coding RNAs (ncRNAs) are involved various physiological processes. Tumor-derived exosomal ncRNAs induce M2 macrophage polarization through signaling pathway activation, signal transduction, transcriptional post-transcriptional regulation. Conversely, TAM-derived promote proliferation, metastasis, angiogenesis, chemoresistance, immunosuppression. MicroRNAs gene silencing by directly targeting mRNAs, whereas lncRNAs circRNAs act as miRNA sponges to indirectly regulate protein expressions. The of tumor-host is ubiquitous. Current research increasingly focused on the microenvironment. On basis "cancer-immunity cycle" hypothesis, we discuss effects immune T cell exhaustion, overexpression programmed death ligands, create immunosuppressive Furthermore, potential applications prospects clinical biomarkers drug delivery systems. 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Language: Английский

The Metabolic Signature of Macrophage Responses DOI Creative Commons
Antonella Viola, Fabio Munari, Ricardo Sánchez‐Rodríguez

et al.

Frontiers in Immunology, Journal Year: 2019, Volume and Issue: 10

Published: July 3, 2019

Macrophages are a heterogeneous population of immune cells playing several and diverse functions in homeostatic responses. The broad spectrum macrophage depends on both heterogeneity plasticity these cells, which highly specialized sensing the microenvironment modify their properties accordingly. Although it is clear that phenotypes difficult to categorize should be seen as plastic adaptable, they can simplified into two extremes: pro-inflammatory (M1) an anti-inflammatory/pro-resolving (M2) profile. Based this definition, M1 macrophages able start sustain inflammatory responses, secreting cytokines, activating endothelial inducing recruitment other inflamed tissue; hand, M2 promote resolution inflammation, phagocytose apoptotic drive collagen deposition, coordinate tissue integrity, release anti-inflammatory mediators. Dramatic switches cell metabolism accompany phenotypic functional changes macrophages. In particular, rely mainly glycolysis present breaks TCA cycle result accumulation itaconate (a microbicide compound) succinate. Excess succinate leads Hypoxia Inducible Factor 1 (HIF1) stabilization that, turn, activates transcription glycolytic genes, thus sustaining On contrary, more dependent oxidative phosphorylation (OXPHOS), intact provides substrates for complexes electron transport chain (ETC). Moreover, pro- characterized by specific pathways regulate lipids amino acids affect All metabolic adaptations support activities well polarization contexts. aim review discuss recent findings linking metabolism.

Language: Английский

Citations

1502
Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation DOI Open Access
Vinícius Fernandes Cruzat, Marcelo Macedo Rogero, Kevin N. Keane

et al.

Nutrients, Journal Year: 2018, Volume and Issue: 10(11), P. 1564 - 1564

Published: Oct. 23, 2018

Glutamine is the most abundant and versatile amino acid in body. In health disease, rate of glutamine consumption by immune cells similar or greater than glucose. For instance, vitro vivo studies have determined that an essential nutrient for lymphocyte proliferation cytokine production, macrophage phagocytic plus secretory activities, neutrophil bacterial killing. release to circulation availability mainly controlled key metabolic organs, such as gut, liver, skeletal muscles. During catabolic/hypercatabolic situations can become function, but its may be compromised due impairment homeostasis inter-tissue metabolism acids. this reason, currently part clinical nutrition supplementation protocols and/or recommended suppressed individuals. However, a wide range (e.g., ill/critically ill, post-trauma, sepsis, exhausted athletes), it difficult determine whether (oral/enteral parenteral) should based on plasma/bloodstream concentration (also known glutaminemia). Although beneficial immune-based effects are already established, many questions evidence positive outcomes still remain presented. Therefore, paper provides integrated review how organs important system. We also discuss action, issues related catabolic situations.

Language: Английский

Citations

890
PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer DOI Creative Commons
Antonino Glaviano, Aaron Song Chuan Foo, Hiu Yan Lam

et al.

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Aug. 18, 2023

Abstract The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, growth, and cycle progression. Growth factor signalling to transcription factors the PAM axis regulated by multiple cross-interactions with several other pathways, dysregulation of can predispose cancer development. most frequently activated human often implicated resistance anticancer therapies. Dysfunction components this such as hyperactivity PI3K, loss function PTEN, gain-of-function AKT, are notorious drivers treatment disease progression cancer. In review we highlight major dysregulations cancer, discuss results AKT mTOR inhibitors monotherapy co-administation antineoplastic agents clinical trials strategy for overcoming resistance. Finally, mechanisms targeted therapies, including immunology immunotherapies also discussed.

Language: Английский

Citations

774
M2b macrophage polarization and its roles in diseases DOI Creative Commons
Lexun Wang,

Sheng-xi Zhang,

Huijuan Wu

et al.

Journal of Leukocyte Biology, Journal Year: 2018, Volume and Issue: 106(2), P. 345 - 358

Published: Dec. 21, 2018

Macrophages play an important role in a wide variety of physiologic and pathologic processes. Plasticity functional polarization are hallmarks macrophages. commonly exist two distinct subsets: classically activated macrophages (M1) alternatively (M2). M2b, subtype M2 macrophages, has attracted increasing attention over the past decade due to its strong immune-regulated anti-inflammatory effects. A stimuli multiple factors modulate M2b macrophage vitro vivo. possess both protective pathogenic roles various diseases. Understanding mechanisms activation modulation their might provide great perspective for design novel therapeutic strategies. The purpose this review is discuss current knowledge polarization, diseases polarization.

Language: Английский

Citations

693
Mesenchymal stromal cell-derived exosomes attenuate myocardial ischaemia-reperfusion injury through miR-182-regulated macrophage polarization DOI Creative Commons
Jinxuan Zhao, Xueling Li, Jiaxin Hu

et al.

Cardiovascular Research, Journal Year: 2019, Volume and Issue: 115(7), P. 1205 - 1216

Published: Feb. 7, 2019

Mesenchymal stromal cells (MSCs) gradually become attractive candidates for cardiac inflammation modulation, yet understanding of the mechanism remains elusive. Strikingly, recent studies indicated that exosomes secreted by MSCs might be a novel beneficial effect transplantation after myocardial infarction. We therefore explored role MSC-derived (MSC-Exo) in immunomodulation macrophages ischaemia/reperfusion (I/R) and its implications injury repair. Exosomes were isolated from supernatant using gradient centrifugation method. Administration MSC-Exo to mice through intramyocardial injection I/R reduced infarct size alleviated level heart serum. Systemic depletion with clodronate liposomes abolished curative effects MSC-Exo. modified polarization M1 M2 both vivo vitro. miRNA sequencing bioinformatics analysis implicated miR-182 as potent candidate mediator macrophage toll-like receptor 4 (TLR4) downstream target. Diminishing partially attenuated modulation polarization. Likewise, knock down TLR4 also conferred cardioprotective efficacy mouse model I/R. Our data indicate attenuates via shuttling modifies status macrophages. This study sheds new light on application potential therapeutic tool injury.

Language: Английский

Citations

606
Properties and functions of adipose tissue macrophages in obesity DOI Open Access

Lucia Russo,

Carey N. Lumeng

Immunology, Journal Year: 2018, Volume and Issue: 155(4), P. 407 - 417

Published: Sept. 19, 2018

Summary The expansion of adipose tissue (AT) in obesity is accompanied by the accumulation immune cells that contribute to a state low‐grade, chronic inflammation and dysregulated metabolism. Adipose macrophages ( ATM s) represent most abundant class leukocytes AT are involved regulation several regulatory physiological processes, such as remodeling insulin sensitivity. With progressive obesity, s key mediators meta‐inflammation, resistance impairment adipocyte function. While macrophage recruitment from blood monocytes critical component generation inflammation, new studies have revealed role for proliferation early stages sustaining inflammation. In addition, more complex range activation states than previous M1/M2 model, existence different profiles between human animal models. This review will summarize current understanding mechanisms function relation type 2 diabetes, depot origin, other dendritic cells, with hopes emphasizing nodes can potentially be targeted prevent treat obesity‐related metabolic disorders.

Language: Английский

Citations

510
Single-Cell Genomics Reveals a Novel Cell State During Smooth Muscle Cell Phenotypic Switching and Potential Therapeutic Targets for Atherosclerosis in Mouse and Human DOI Open Access
Huize Pan, Chenyi Xue, Benjamin J. Auerbach

et al.

Circulation, Journal Year: 2020, Volume and Issue: 142(21), P. 2060 - 2075

Published: Sept. 23, 2020

Background: Smooth muscle cells (SMCs) play significant roles in atherosclerosis via phenotypic switching, a pathological process which SMC dedifferentiation, migration, and transdifferentiation into other cell types. Yet how SMCs contribute to the pathophysiology of remains elusive. Methods: To reveal trajectories during identify molecular targets for disease therapy, we combined fate mapping single-cell RNA sequencing both mouse human atherosclerotic plaques. We also performed biology experiments on isolated SMC-derived cells, conducted integrative genomics, used pharmacological studies targeting vivo vitro. Results: found that transitioned an intermediate state atherosclerosis, was plaques carotid coronary arteries. termed “SEM” (stem cell, endothelial monocyte), were multipotent could differentiate macrophage-like fibrochondrocyte-like as well return toward phenotype. Retinoic acid (RA) signaling identified regulator SEM transition, RA dysregulated symptomatic atherosclerosis. Human genomics revealed enrichment genome-wide association study signals artery target gene loci correlation between risk alleles repressed expression these genes. Activation by all-trans RA, anticancer drug acute promyelocytic leukemia, blocked transition reduced burden, promoted fibrous cap stability. Conclusions: Integration cell-specific mapping, genetics adds novel insights complexity reveals regulatory pathways therapeutic transitions cardiovascular disease.

Language: Английский

Citations

440
Exosome-shuttled miR-216a-5p from hypoxic preconditioned mesenchymal stem cells repair traumatic spinal cord injury by shifting microglial M1/M2 polarization DOI Creative Commons
Wei Liu,

Yuluo Rong,

Jiaxing Wang

et al.

Journal of Neuroinflammation, Journal Year: 2020, Volume and Issue: 17(1)

Published: Feb. 4, 2020

Spinal cord injury (SCI) can lead to severe motor and sensory dysfunction with high disability mortality. In recent years, mesenchymal stem cell (MSC)-secreted nano-sized exosomes have shown great potential for promoting functional behavioral recovery following SCI. However, MSCs are usually exposed normoxia in vitro, which differs greatly from the hypoxic micro-environment vivo. Thus, main purpose of this study was determine whether derived under hypoxia (HExos) exhibit greater effects on than those (Exos) SCI mice seek underlying mechanism.Electron microscope, nanoparticle tracking analysis (NTA), western blot were applied characterize differences between Exos HExos group. A model vivo a series vitro experiments performed compare therapeutic two groups. Next, miRNA microarray rescue conducted verify role exosomal Western blot, luciferase activity, RNA-ChIP used investigate mechanisms.Our results indicate that promote by shifting microglial polarization M1 M2 phenotype vitro. array showed miR-216a-5p be most enriched potentially involved HExos-mediated polarization. TLR4 identified as target downstream gene miR-216a-5p/TLR4 axis confirmed gain- loss-of-function experiments. Finally, we found TLR4/NF-κB/PI3K/AKT signaling cascades may modulation miR-216a-5p.Hypoxia preconditioning represents promising effective approach optimize actions MSC-derived combination miRNAs present minimally invasive method treating

Language: Английский

Citations

421
Melatonin-stimulated MSC-derived exosomes improve diabetic wound healing through regulating macrophage M1 and M2 polarization by targeting the PTEN/AKT pathway DOI Creative Commons
Wei Liu, Muyu Yu, Dong Xie

et al.

Stem Cell Research & Therapy, Journal Year: 2020, Volume and Issue: 11(1)

Published: June 29, 2020

Abstract Background After surgery, wound recovery in diabetic patients may be disrupted due to delayed inflammation, which can lead undesired consequences, and there is currently a lack of effective measures address this issue. Mesenchymal stem cell (MSC)-derived exosomes (Exo) have been proven appropriate candidates for healing through the anti-inflammatory effects. In study, we investigated whether melatonin (MT)-pretreated MSCs-derived (MT-Exo) could exert superior effects on healing, attempted elucidate underlying mechanism. Methods For evaluation effect MT-Exo, vitro vivo studies were performed. research, detected secreted levels inflammation-related factors, such as IL-1β, TNF-α IL-10 via ELISA relative gene expression TNF-α, IL-10, Arg-1 iNOS qRT-PCR PTEN, AKT p-AKT by Western blotting. established air pouch model streptozotocin (STZ)-treated model, evaluated MT-Exo flow cytometry, optical imaging, H&E staining, Masson trichrome immunohistochemical immunofluorescence, (α-SMA, collagen I III). Results significantly suppressed pro-inflammatory factors IL-1β reduced iNOS, while promoting factor along with increasing Arg-1, compared that PBS, LPS Exo groups vitro. This was mediated increased ratio M2 polarization M1 upregulating PTEN inhibiting phosphorylation AKT. Similarly, promoted wounds thereby further facilitating angiogenesis synthesis vivo. Conclusions promote suppressing inflammatory response, achieved activating PTEN/AKT signalling pathway, pretreatment MT proved promising method treating healing. Graphical abstract: promotes regulating macrophage polarization.

Language: Английский

Citations

387
Targeting Tyro3, Axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment DOI Creative Commons
K. Myers, Sarah R. Amend, Kenneth J. Pienta

et al.

Molecular Cancer, Journal Year: 2019, Volume and Issue: 18(1)

Published: May 14, 2019

Tumor-associated macrophages are an abundant cell type in the tumor microenvironment. These serve as a promising target for treatment of cancer due to their roles promoting progression and simultaneous immunosuppression. The TAM receptors (Tyro3, Axl MerTK) therapeutic targets on tumor-associated macrophages. family receptor tyrosine kinases with shared ligands Gas6 Protein S that skew macrophage polarization towards pro-tumor M2-like phenotype. In macrophages, also promote apoptotic clearance, tumor-promoting process called efferocytosis. bind "eat-me" signal phosphatidylserine membranes using bridging ligands. Post-efferocytosis, further polarized phenotype secrete increased levels immunosuppressive cytokines. Since M2 efferocytosis processes, exciting therapy. Current receptor-directed therapies preclinical development clinical trials may have anti-cancer effects though impacting function addition cells.

Language: Английский

Citations

338