Exosomes derived from alcohol-treated hepatocytes horizontally transfer liver specific miRNA-122 and sensitize monocytes to LPS

Momen-Heravi, Fatemeh; Bala, Shashi; Kodys, Karen; Szabó, Gyöngyi

doi:10.1038/srep09991

Cited by 298 publications

(351 citation statements)

References 51 publications

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“…Indeed, we showed that, unlike EVN, EVF do not suppress proliferation or expression of fibrosis- or activation-related genes in HSC. Since inflammatory pathways in the liver have been linked to EV communication between hepatocytes and monocytes [65], an interesting area for future study will be to determine whether the therapeutic actions of EVN in fibrosis are in part attributable to the action of EV miRs and/or other EV constituents on pro-inflammatory gene expression and regulation of inflammatory cell function.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic effects of serum extracellular vesicles in liver fibrosis

Chen

Kemper

et al. 2018

J of Extracellular Vesicle

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The lack of approved therapies for hepatic fibrosis seriously limits medical management of patients with chronic liver disease. Since extracellular vesicles (EVs) function as conduits for intercellular molecular transfer, we investigated if EVs from healthy individuals have anti-fibrotic properties. Hepatic fibrogenesis or fibrosis in carbon tetrachloride (CCl4)- or thioacetic acid-induced liver injury models in male or female mice were suppressed by serum EVs from normal mice (EVN) but not from fibrotic mice (EVF). CCl4-treated mice undergoing EVN therapy also exhibited reduced levels of hepatocyte death, inflammatory infiltration, circulating AST/ALT levels and hepatic or circulating pro-inflammatory cytokines. Hepatic histology, liver function tests or circulating proinflammatory cytokine levels were unaltered in control mice receiving EVN. As determined using PKH26-labelled EVN, principal target cells included hepatic stellate cells (HSC; a normally quiescent fibroblastic cell that undergoes injury-induced activation and produces fibrosis during chronic injury) or hepatocytes which showed increased EVN binding after, respectively, activation or exposure to CCl4. In vitro, EVN decreased proliferation and fibrosis-associated molecule expression in activated HSC, while reversing the inhibitory effects of CCl4 or ethanol on hepatocyte proliferation. In mice, microRNA-34c, -151-3p, -483-5p, -532-5p and -687 were more highly expressed in EVN than EVF and mimics of these microRNAs (miRs) individually suppressed fibrogenic gene expression in activated HSC. A role for these miRs in contributing to EVN actions was shown by the ability of their corresponding antagomirs to individually and/or collectively block the therapeutic effects of EVN on activated HSC or injured hepatocytes. Similarly, the activated phenotype of human LX-2 HSC was attenuated by serum EVs from healthy human subjects and contained higher miR-34c, -151-3p, -483-5p or -532-5p than EVs from hepatic fibrosis patients. In conclusion, serum EVs from normal healthy individuals are inherently anti-fibrogenic and anti-fibrotic, and contain microRNAs that have therapeutic actions in activated HSC or injured hepatocytes.Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; CCl4: carbon tetrachloride; CCN2: connective tissue growth factor; E: eosin; EGFP: enhanced green fluorescent protein; EVs: extracellular vesicles; EVF: serum EVs from mice with experimental hepatic fibrosis; EVN: serum EVs from normal mice; H: hematoxylin; HSC: hepatic stellate cell; IHC: immunohistochemistry; IL: interleukin; MCP-1: monocyte chemotactic protein-1; miR: microRNA; mRNA: messenger RNA; NTA: nanoparticle tracking analysis; PCNA: proliferating cell nuclear antigen; qRT-PCR: quantitative real-time polymerase chain reaction; SDS-PAGE: sodium dodecyl sulphate – polyacrylamide gel electrophoresis; αSMA: alpha smooth muscle actin; TAA: thioacetic acid; TG: transgenic; TGF-β: transforming growth factor beta; TEM: transmission electron microscopy; TNFα...

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Section: Discussionmentioning

confidence: 99%

Therapeutic effects of serum extracellular vesicles in liver fibrosis

Chen

Kemper

et al. 2018

J of Extracellular Vesicle

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“…Following EV-mediated transfer of miRNA122 to monocytes, the monocytes become highly sensitive to LPS, upregulating their secretion of IL-1β and TNF-α compared with that after LPS treatment alone. This EV-mediated sensitization of monocytes could promote a state of chronic, systemic inflammation that further exacerbates the diagnosis phenotype and comorbidities in patients with liver disease (59,60 (44). Thus, tumor-derived EVs can function at multiple levels to facilitate tumor growth and metastasis.…”

Section: Suppression Of Immune Responses By Evsmentioning

confidence: 99%

Regulation of chronic inflammatory and immune processes by extracellular vesicles

Robbins

Dorronsoro

Booker

2016

Journal of Clinical Investigation

231

195

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“…In addition, secreted microRNAs can silence their target genes in remote tissues, thereby playing a role in cell-to-cell communication 28,29 .…”

Section: Tnfα and Lps Enhance Secretion Of Mir-122mentioning

confidence: 99%

Inflammation-Induced Expression and Secretion of MicroRNA 122 Leads to Reduced Blood Levels of Kidney-Derived Erythropoietin and Anemia

et al. 2016

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BACKGROUND AIM Anemia is commonly associated with acute and chronic inflammation, but the mechanisms of their interaction are not clear. We investigated whether microRNA 122 (MIR122), which is generated in the liver and is secreted into the blood, is involved in the development of anemia associated with inflammation. METHODS We characterized the primary transcript of the human liverspecific MIR122 using northern blot, quantitative real-time PCR, and 3' and 5' RACE analyses. We studied regulation of MIR122 in human hepatocellular carcinoma (HCC) cell lines (Huh7 and HepG2) as well as in C57BL/6 and mice with disruption of the tumor necrosis factor gene (Tnf). Liver tissues were collected and analyzed by bioluminescence imaging or immunofluorescence. Inflammation in mice was induced by lipopolysaccharide (LPS) or by cerulein injections. Mice were given 4 successive injections of LPS, leading to inflammation-induced anemia. Steatohepatitis was induced with a choline-deficient high-fat diet. Hemolytic anemia was stimulated by phenylhydrazine injection. MIR122 was inhibited in mice by tail-vein injection of antogomiR-122 (an oligonucleotide antagonist of MIR122). MicroRNA and mRNA levels were determined by quantitative real time PCR. RESULTS The primary transcript of MIR122 spanned 5 kb, comprising 3 exons; the third encodes MIR122. Within the MIR122 promoter region we identified a nuclear factor-B (NF-B) binding site and demonstrated that RELA, as well as activators of NF-B (TNF and LPS), increased promoter activity of MIR122. Administration of LPS to mice induced secretion of MIR122 into blood, which required TNF. Secreted MIR122 reached the kidney and reduced expression of erythropoietin (Epo), which we identified as a MIR122 target gene. Injection of mice with antagomiR-122 increased blood levels of EPO, reticulocytes, and hemoglobin. We found an inverse relationship between blood levels of MIR122 and EPO in mice with acute pancreatitis or steatohepatitis, and also in patients with acute inflammation. CONCLUSION In mice, we found that LPS-induced inflammation increases blood levels of MIR122, which reduces expression of Epo in the kidney; this is a mechanism of inflammation-induced anemia. Strategies to block MIR122 in patients with inflammation could reduce the development or progression of anemia. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT AbstractBackground & Aim: Anemia is commonly associated with acute and chronic inflammation, but the mechanisms of their interaction are not clear. We investigated whether microRNA 122 (MIR122),...

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Exosomes derived from alcohol-treated hepatocytes horizontally transfer liver specific miRNA-122 and sensitize monocytes to LPS

Cited by 298 publications

References 51 publications

Therapeutic effects of serum extracellular vesicles in liver fibrosis

Therapeutic effects of serum extracellular vesicles in liver fibrosis

Regulation of chronic inflammatory and immune processes by extracellular vesicles

Inflammation-Induced Expression and Secretion of MicroRNA 122 Leads to Reduced Blood Levels of Kidney-Derived Erythropoietin and Anemia

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