Extracellular vesicle-mediated macrophage activation: An insight into the mechanism of thioredoxin-mediated immune activation.
Aldehydes
/ immunology
Animals
Antibiotics, Antineoplastic
/ pharmacology
Cell Line
Culture Media, Conditioned
/ chemistry
Doxorubicin
/ pharmacology
Extracellular Vesicles
/ chemistry
Gene Expression Regulation
Glycolysis
/ drug effects
Hepatocytes
/ chemistry
Macrophage Activation
/ drug effects
Mice
Mitochondria
/ drug effects
Myocytes, Cardiac
/ chemistry
NF-E2-Related Factor 2
/ genetics
NF-kappa B
/ genetics
Oxidation-Reduction
RAW 264.7 Cells
Rats
Thioredoxins
/ genetics
Extracellular vesicles
Macrophage activation
NFκB
Nrf-2
Thioredoxin 1
Journal
Redox biology
ISSN: 2213-2317
Titre abrégé: Redox Biol
Pays: Netherlands
ID NLM: 101605639
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
01
02
2019
revised:
28
05
2019
accepted:
31
05
2019
pubmed:
6
7
2019
medline:
29
2
2020
entrez:
6
7
2019
Statut:
ppublish
Résumé
Extracellular vesicles (EVs) generated from redox active anticancer drugs are released into the extracellular environment. These EVs contain oxidized molecules and trigger inflammatory responses by macrophages. Using a mouse model of doxorubicin (DOX)-induced tissue injury, we previously found that the major sources of circulating EVs are from heart and liver, organs that are differentially affected by DOX. Here, we investigated the effects of EVs from cardiomyocytes and those from hepatocytes on macrophage activation. EVs from H9c2 rat cardiomyocytes (H9c2 EVs) and EVs from FL83b mouse hepatocytes (FL83 b EVs) have different levels of protein-bound 4-hydroxynonenal and thus different immunostimulatory effects on mouse RAW264.7 macrophages. H9c2 EVs but not FL83 b EVs induced both pro-inflammatory and anti-inflammatory macrophage activation, mediated by NFκB and Nrf-2 pathways, respectively. DOX enhanced the effects of H9c2 EVs but not FL83 b EVs. While EVs from DOX-treated H9c2 cells (H9c2 DOXEVs) suppressed mitochondrial respiration and increased glycolysis of macrophages, EVs from DOX-treated FL83b cells (FL83b DOXEVs) enhanced mitochondrial reserve capacity. Mechanistically, the different immunostimulatory functions of H9c2 EVs and FL83 b EVs are regulated, in part, by the redox status of the cytoplasmic thioredoxin 1 (Trx1) of macrophages. H9c2 DOXEVs lowered the level of reduced Trx1 in cytoplasm while FL83b DOXEVs did the opposite. Trx1 overexpression alleviated the effect of H9c2 DOXEVs on NFκB and Nrf-2 activation and prevented the upregulation of their target genes. Our findings identify EVs as a novel Trx1-mediated redox mediator of immune response, which greatly enhances our understanding of innate immune responses during cancer therapy.
Identifiants
pubmed: 31276937
pii: S2213-2317(19)30166-1
doi: 10.1016/j.redox.2019.101237
pmc: PMC6612011
pii:
doi:
Substances chimiques
Aldehydes
0
Antibiotics, Antineoplastic
0
Culture Media, Conditioned
0
NF-E2-Related Factor 2
0
NF-kappa B
0
Nfe2l2 protein, mouse
0
Txn1 protein, mouse
0
Thioredoxins
52500-60-4
Doxorubicin
80168379AG
4-hydroxy-2-nonenal
K1CVM13F96
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101237Subventions
Organisme : NIGMS NIH HHS
ID : P20 GM121327
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA177558
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA217934
Pays : United States
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
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