Comprehensive characterization of hepatocyte-derived extracellular vesicles identifies direct miRNA-based regulation of hepatic stellate cells and DAMP-based hepatic macrophage IL-1β and IL-17 upregulation in alcoholic hepatitis mice.

Animals DNA, Mitochondrial / metabolism Down-Regulation / physiology Extracellular Vesicles / metabolism Hepatic Stellate Cells / metabolism Hepatitis, Alcoholic / metabolism Hepatocytes / metabolism Humans Interleukin-17 / metabolism Interleukin-1beta / metabolism Liver / metabolism Macrophages / metabolism Male Mice Mice, Inbred C57BL MicroRNAs / metabolism Up-Regulation / physiology
AH DAMPs HSC activation Hepatic macrophage activation Hepatocyte-derived EVs miRNAs

Journal

Journal of molecular medicine (Berlin, Germany)
ISSN: 1432-1440
Titre abrégé: J Mol Med (Berl)
Pays: Germany
ID NLM: 9504370

Informations de publication

Date de publication:
07 2020
Historique:
received: 03 01 2020
accepted: 14 05 2020
revised: 11 05 2020
pubmed: 20 6 2020
medline: 13 7 2021
entrez: 20 6 2020
Statut: ppublish

Résumé

Extracellular vesicles (EVs) have been growingly recognized as biomarkers and mediators of alcoholic liver disease (ALD) in human and mice. Here we characterized hepatocyte-derived EVs (HC-EVs) and their cargo for their biological functions in a novel murine model that closely resembles liver pathology observed in patients with alcoholic hepatitis (AH), the most severe spectrum of ALD. The numbers of circulating EVs and HC-EVs were significantly increased by 10-fold in AH mice compared with control mice. The miRNA (miR)-seq analysis detected 20 upregulated and 4 downregulated miRNAs (P < 0.001-0.05) in AH-HC-EVs. Treatment of murine primary hepatic stellate cells (HSCs) with AH-HC-EVs induced α-SMA (P < 0.05) and Col1a1 (P < 0.001). Smad7 and Nr1d2 genes, which were downregulated in HSCs from the AH mice, were predicted targets of 20 miRs upregulated in AH-HC-EVs. Among them were miR-27a and miR-181 which upon transfection in HSCs, indeed repressed Nr1d2, the quiescent HSC marker. AH-HC-EVs were also enriched with organelle proteins and mitochondrial DNA (10-fold, P < 0.05) and upregulated IL-1β and IL-17 production by hepatic macrophages (HMs) from AH mice in a TLR9-dependent manner. These results demonstrate HC-EV release is intensified in AH and suggest that AH-HC-EVs orchestrate liver fibrogenesis by directly targeting the quiescent HSC transcripts via a unique set of miRNAs and by amplifying HSC activation via DAMP-based induction of profibrogenic IL-1β and IL-17 by HMs. KEY MESSAGES: • Circulating EVs and HC-EVs were increased in AH mice compared with control mice • AH-HC-EVs were enriched in miRNAs, organelle proteins, and mitochondrial DNA • AH-HC-EVs increased cytokine production by AH-HMs in a TLR9-dependent manner.

Identifiants

DOI: 10.1007/s00109-020-01926-7 PMID: 32556367 PMC: PMC7810220
pubmed: 32556367
doi: 10.1007/s00109-020-01926-7
pii: 10.1007/s00109-020-01926-7
pmc: PMC7810220
mid: NIHMS1658484
doi:

Substances chimiques

DNA, Mitochondrial 0
IL1B protein, mouse 0
Interleukin-17 0
Interleukin-1beta 0
MicroRNAs 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

1021-1034

Subventions

Organisme : NIGMS NIH HHS
ID : P41 GM103493
Pays : United States
Organisme : NHLBI NIH HHS
ID : U54 HL108460
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01AA027681
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA018663
Pays : United States
Organisme : VA
ID : IK6BX004205
Pays : United States
Organisme : BLRD VA
ID : I01 BX001991
Pays : United States
Organisme : NIAAA NIH HHS
ID : R24 AA012885
Pays : United States
Organisme : NIH HHS
ID : U54HL108460
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA028134
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA027681
Pays : United States
Organisme : BLRD VA
ID : IK6 BX004205
Pays : United States
Organisme : NIH HHS
ID : S10 OD023527
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA022489
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA022489
Pays : United States
Organisme : Japan Society for the Promotion of Science
ID : JP16H06872
Pays : International
Organisme : Japan Society for the Promotion of Science
ID : JP17K09419
Pays : International
Organisme : NIH HHS
ID : P41 GM103493
Pays : United States
Organisme : NIAAA NIH HHS
ID : R21 AA023574
Pays : United States
Organisme : NIAAA NIH HHS
ID : P50 AA011999
Pays : United States
Organisme : VA
ID : I01BX001991
Pays : United States
Organisme : NIH HHS
ID : DK082451
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01AA018663
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK082451
Pays : United States
Organisme : NIAAA NIH HHS
ID : P50AA011999
Pays : United States
Organisme : NIAAA NIH HHS
ID : R24AA012885
Pays : United States

Références

Yin M, Wheeler MD, Kono H, Bradford BU, Gallucci RM, Luster MI, Thurman RG (1999) Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology 117:942–952
doi: 10.1016/S0016-5085(99)70354-9
Mathurin P (2009) Alcohol and the liver. Gastroenterologie clinique et biologique 33:840–849
doi: 10.1016/j.gcb.2009.06.004
Nanji AA, Su GL, Laposata M, French SW (2002) Pathogenesis of alcoholic liver disease--recent advances. Alcohol Clin Exp Res 26:731–736
pubmed: 12045483
Feldstein AE, Gores GJ (2005) Apoptosis in alcoholic and nonalcoholic steatohepatitis. Frontiers in bioscience : a journal and virtual library 10:3093–3099
doi: 10.2741/1765
Thurman RG, Bradford BU, Iimuro Y, Knecht KT, Connor HD, Adachi Y, Wall C, Arteel GE, Raleigh JA, Forman DT, Mason RP (1997) Role of Kupffer cells, endotoxin and free radicals in hepatotoxicity due to prolonged alcohol consumption: studies in female and male rats. J Nutr 127:903S–906S
doi: 10.1093/jn/127.5.903S
Nanji AA (2002) Role of Kupffer cells in alcoholic hepatitis. Alcohol 27:13–15
doi: 10.1016/S0741-8329(02)00207-0
Rose ML, Rusyn I, Bojes HK, Belyea J, Cattley RC, Thurman RG (2000) Role of Kupffer cells and oxidants in signaling peroxisome proliferator-induced hepatocyte proliferation. Mutat Res 448:179–192
doi: 10.1016/S0027-5107(99)00235-3
Eguchi A, Lazaro RG, Wang J, Kim J, Povero D, Willliams B, Ho SB, Starkel P, Schnabl B, Ohno-Machado L et al (2017) Extracellular vesicles released by hepatocytes from gastric infusion model of alcoholic liver disease contain a MicroRNA barcode that can be detected in blood. Hepatology 65:475–490
doi: 10.1002/hep.28838
Lazaro R, Wu R, Lee S, Zhu NL, Chen CL, French SW, Xu J, Machida K, Tsukamoto H (2015) Osteopontin deficiency does not prevent but promotes alcoholic neutrophilic hepatitis in mice. Hepatology 61:129–140
doi: 10.1002/hep.27383
Yanez-Mo M, Siljander PR, Andreu Z, Zavec AB, Borras FE, Buzas EI, Buzas K, Casal E, Cappello F, Carvalho J et al (2015) Biological properties of extracellular vesicles and their physiological functions. Journal of extracellular vesicles 4:27066
doi: 10.3402/jev.v4.27066
Gao B, Ahmad MF, Nagy LE, Tsukamoto H (2019) Inflammatory pathways in alcoholic steatohepatitis. J Hepatol 70:249–259
doi: 10.1016/j.jhep.2018.10.023
Khanova E, Wu R, Wang W, Yan R, Chen Y, French SW, Llorente C, Pan SQ, Yang Q, Li Y, Lazaro R, Ansong C, Smith RD, Bataller R, Morgan T, Schnabl B, Tsukamoto H (2018) Pyroptosis by caspase11/4-gasdermin-D pathway in alcoholic hepatitis in mice and patients. Hepatology 67:1737–1753
doi: 10.1002/hep.29645
Lai KKY, Kweon SM, Chi F, Hwang E, Kabe Y, Higashiyama R, Qin L, Yan R, Wu RP, Lai K, Fujii N, French S, Xu J, Wang JY, Murali R, Mishra L, Lee JS, Ntambi JM, Tsukamoto H (2017) Stearoyl-CoA desaturase promotes liver fibrosis and tumor development in mice via a Wnt positive-signaling loop by stabilization of low-density lipoprotein-receptor-related proteins 5 and 6. Gastroenterology 152:1477–1491
doi: 10.1053/j.gastro.2017.01.021
Xu J, Chi F, Guo T, Punj V, Lee WN, French SW, Tsukamoto H (2015) NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation. J Clin Invest 125:1579–1590
doi: 10.1172/JCI76468
Anders S, Huber W (2010) Differential expression analysis for sequence count data. Genome Biol 11:R106
doi: 10.1186/gb-2010-11-10-r106
Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc B 57:289–300
Kim J, Levy E, Ferbrache A, Stepanowsky P, Farcas C, Wang S, Brunner S, Bath T, Wu Y, Ohno-Machado L (2014) MAGI: a Node.js web service for fast microRNA-Seq analysis in a GPU infrastructure. Bioinformatics 30:2826–2827
doi: 10.1093/bioinformatics/btu377
Vlachos IS, Zagganas K, Paraskevopoulou MD, Georgakilas G, Karagkouni D, Vergoulis T, Dalamagas T, Hatzigeorgiou AG (2015) DIANA-miRPath v3.0: deciphering microRNA function with experimental support. Nucleic Acids Res 43:W460–W466
doi: 10.1093/nar/gkv403
Wang H, Qian WJ, Mottaz HM, Clauss TR, Anderson DJ, Moore RJ, Camp DG 2nd, Khan AH, Sforza DM, Pallavicini M et al (2005) Development and evaluation of a micro- and nanoscale proteomic sample preparation method. J Proteome Res 4:2397–2403
doi: 10.1021/pr050160f
Yang J, Yin L, Lessner FH, Nakayasu ES, Payne SH, Fixen KR, Gallagher L, Harwood CS (2017) Genes essential for phototrophic growth by a purple alphaproteobacterium. Environ Microbiol 19:3567–3578
doi: 10.1111/1462-2920.13852
Bantscheff M, Schirle M, Sweetman G, Rick J, Kuster B (2007) Quantitative mass spectrometry in proteomics: a critical review. Anal Bioanal Chem 389:1017–1031
doi: 10.1007/s00216-007-1486-6
Schulze WX, Usadel B (2010) Quantitation in mass-spectrometry-based proteomics. Annu Rev Plant Biol 61:491–516
doi: 10.1146/annurev-arplant-042809-112132
Garcia-Martinez I, Santoro N, Chen Y, Hoque R, Ouyang X, Caprio S, Shlomchik MJ, Coffman RL, Candia A, Mehal WZ (2016) Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J Clin Invest 126:859–864
doi: 10.1172/JCI83885
Tkach M, Thery C (2016) Communication by extracellular vesicles: where we are and where we need to go. Cell 164:1226–1232
doi: 10.1016/j.cell.2016.01.043
Liu X, Rosenthal SB, Meshgin N, Baglieri J, Musallam SG, Diggle K, Lam K, Wu R, Pan SQ, Chen Y, Dorko K, Presnell S, Benner C, Hosseini M, Tsukamoto H, Brenner D, Kisseleva T (2020) Primary alcohol-activated human and mouse hepatic stellate cells share similarities in gene-expression profiles. Hepatology communications 4:606–626
doi: 10.1002/hep4.1483
Liu X, Xu J, Brenner DA, Kisseleva T (2013) Reversibility of liver fibrosis and inactivation of fibrogenic myofibroblasts. Curr Pathobiol Rep 1:209–214
doi: 10.1007/s40139-013-0018-7
Hirsova P, Ibrahim SH, Verma VK, Morton LA, Shah VH, LaRusso NF, Gores GJ, Malhi H (2016) Extracellular vesicles in liver pathobiology: small particles with big impact. Hepatology 64:2219–2233
doi: 10.1002/hep.28814
Povero D, Panera N, Eguchi A, Johnson CD, Papouchado BG, de Araujo HL, Pinatel EM, Alisi A, Nobili V, Feldstein AE (2015) Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-gamma. Cellular and molecular gastroenterology and hepatology 1:646–663 e644
doi: 10.1016/j.jcmgh.2015.07.007
Meng F, Wang K, Aoyama T, Grivennikov SI, Paik Y, Scholten D, Cong M, Iwaisako K, Liu X, Zhang M, Österreicher CH, Stickel F, Ley K, Brenner DA, Kisseleva T (2012) Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 143:765–776 e763
doi: 10.1053/j.gastro.2012.05.049
Fabre T, Kared H, Friedman SL, Shoukry NH (2014) IL-17A enhances the expression of profibrotic genes through upregulation of the TGF-beta receptor on hepatic stellate cells in a JNK-dependent manner. J Immunol 193:3925–3933
doi: 10.4049/jimmunol.1400861
Bhan U, Ballinger MN, Zeng X, Newstead MJ, Cornicelli MD, Standiford TJ (2010) Cooperative interactions between TLR4 and TLR9 regulate interleukin 23 and 17 production in a murine model of gram negative bacterial pneumonia. PLoS One 5:e9896
doi: 10.1371/journal.pone.0009896
Salloum N, Hussein HM, Jammaz R, Jiche S, Uthman IW, Abdelnoor AM, Rahal EA (2018) Epstein-Barr virus DNA modulates regulatory T-cell programming in addition to enhancing interleukin-17A production via Toll-like receptor 9. PLoS One 13:e0200546
doi: 10.1371/journal.pone.0200546
Mansouri A, Gattolliat CH, Asselah T (2018) Mitochondrial dysfunction and signaling in chronic liver diseases. Gastroenterology 155:629–647
doi: 10.1053/j.gastro.2018.06.083
Hoek JB, Cahill A, Pastorino JG (2002) Alcohol and mitochondria: a dysfunctional relationship. Gastroenterology 122:2049–2063
doi: 10.1053/gast.2002.33613
Szabo G, Bala S (2013) MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol 10:542–552
doi: 10.1038/nrgastro.2013.87
Kitano M, Bloomston PM (2016) Hepatic stellate cells and microRNAs in pathogenesis of liver fibrosis. J Clin Med 5. https://doi.org/10.3390/jcm5030038
MR MG, Staggs VS, Sharpe MR, Lee WM, Jaeschke H, Acute Liver Failure Study G (2014) Serum mitochondrial biomarkers and damage-associated molecular patterns are higher in acetaminophen overdose patients with poor outcome. Hepatology 60:1336–1345
He Y, Feng D, Li M, Gao Y, Ramirez T, Cao H, Kim SJ, Yang Y, Cai Y, Ju C, Wang H, Li J, Gao B (2017) Hepatic mitochondrial DNA/Toll-like receptor 9/MicroRNA-223 forms a negative feedback loop to limit neutrophil overactivation and acetaminophen hepatotoxicity in mice. Hepatology 66:220–234
doi: 10.1002/hep.29153
Eguchi A, Kostallari E, Feldstein AE, Shah VH (2019) Extracellular vesicles, the liquid biopsy of the future. J Hepatol 70:1292–1294
doi: 10.1016/j.jhep.2019.01.030
Eguchi A, Feldstein AE (2018) Extracellular vesicles in non-alcoholic and alcoholic fatty liver diseases. Liver Res 2:30–34
doi: 10.1016/j.livres.2018.01.001

Auteurs

Akiko Eguchi (A)

Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan. akieguchi@clin.medic.mie-u.ac.jp.
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA. akieguchi@clin.medic.mie-u.ac.jp.
Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA. akieguchi@clin.medic.mie-u.ac.jp.
JST, PRETO, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan. akieguchi@clin.medic.mie-u.ac.jp.
ORCID: 0000-0002-0555-2707

Rui Yan (R)

Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA.
Department of Pathology, Keck School of Medicine of the University of Southern California, 1333 San Pablo Street, MMR-402, Los Angeles, CA, 90033, USA.

Stephanie Q Pan (SQ)

Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA.
Department of Pathology, Keck School of Medicine of the University of Southern California, 1333 San Pablo Street, MMR-402, Los Angeles, CA, 90033, USA.

Raymond Wu (R)

Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA.
Department of Pathology, Keck School of Medicine of the University of Southern California, 1333 San Pablo Street, MMR-402, Los Angeles, CA, 90033, USA.

Jihoon Kim (J)

Department of Biomedical Informatics, University of California San Diego, La Jolla, CA, USA.

Yibu Chen (Y)

Bioinformatics Services, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90007, USA.

Charles Ansong (C)

Pacific Northwest National Laboratory, Richland, WA, USA.

Richard D Smith (RD)

Pacific Northwest National Laboratory, Richland, WA, USA.

Mina Tempaku (M)

Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan.

Lucila Ohno-Machado (L)

Department of Biomedical Informatics, University of California San Diego, La Jolla, CA, USA.

Yoshiyuki Takei (Y)

Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan.

Ariel E Feldstein (AE)

Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA.

Hidekazu Tsukamoto (H)

Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA. htsukamo@med.usc.edu.
Department of Pathology, Keck School of Medicine of the University of Southern California, 1333 San Pablo Street, MMR-402, Los Angeles, CA, 90033, USA. htsukamo@med.usc.edu.
Greater Los Angeles VA Healthcare System, Los Angeles, CA, USA. htsukamo@med.usc.edu.

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Comprehensive characterization of...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ADN › ADN mitochondrial › Comprehensive characterization of...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Régulation négative › Comprehensive characterization of...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace extracellulaire › Vésicules extracellulaires › Comprehensive characterization of...
questionsmedicales.fr › Cellules › Cellules étoilées du foie › Comprehensive characterization of...
questionsmedicales.fr › Troubles dus à des produits chimiques › Troubles dus à l'abus d'alcool › Maladies alcooliques du foie › Hépatite alcoolique › Comprehensive characterization of...
questionsmedicales.fr › Cellules › Cellules épithéliales › Hépatocytes › Comprehensive characterization of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Comprehensive characterization of...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Interleukines › Interleukine-17 › Comprehensive characterization of...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Monokines › Interleukine-1 › Interleukine-1 bêta › Comprehensive characterization of...
questionsmedicales.fr › Système digestif › Foie › Comprehensive characterization of...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Phagocytes › Macrophages › Comprehensive characterization of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Comprehensive characterization of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Comprehensive characterization of...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN non traduit › Petit ARN non traduit › microARN › Comprehensive characterization of...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Régulation positive › Comprehensive characterization of...