In Vivo Silencing of A20 via TLR9-Mediated Targeted SiRNA Delivery Potentiates Antitumor Immune Response.
A20 is an ubiquitin-editing enzyme that ensures the transient nature of inflammatory signaling pathways induced by cytokines like TNF-α and IL-1 or pathogens via Toll-like receptor (TLR) pathways. It has been identified as a negative regulator of dendritic cell (DC) maturation and attenuator of thei...
Main Authors: | , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2015-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC4556692?pdf=render |
id |
doaj-7a427a310d524b2f9394b2e9fea93d54 |
---|---|
record_format |
Article |
spelling |
doaj-7a427a310d524b2f9394b2e9fea93d542020-11-25T00:40:51ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01109e013544410.1371/journal.pone.0135444In Vivo Silencing of A20 via TLR9-Mediated Targeted SiRNA Delivery Potentiates Antitumor Immune Response.Floriane C M BraunJens van den BrandtSören ThomasSandra LangeJuliane SchrankClaudia GandGrzegorz K PrzybylskiKatrin SchmoeckelBarbara M BrökerChristian A SchmidtPiotr GrabarczykA20 is an ubiquitin-editing enzyme that ensures the transient nature of inflammatory signaling pathways induced by cytokines like TNF-α and IL-1 or pathogens via Toll-like receptor (TLR) pathways. It has been identified as a negative regulator of dendritic cell (DC) maturation and attenuator of their immunostimulatory properties. Ex vivo A20-depleted dendritic cells showed enhanced expression of pro-inflammatory cytokines and costimulatory molecules, which resulted in hyperactivation of tumor-infiltrating T lymphocytes and inhibition of regulatory T cells. In the present study, we demonstrate that a synthetic molecule consisting of a CpG oligonucleotide TLR9 agonist linked to A20-specific siRNAs silences its expression in TLR9+ mouse dendritic cells in vitro and in vivo. In the B16 mouse melanoma tumor model, silencing of A20 enhances the CpG-triggered induction of NFκB activity followed by elevated expression of IL-6, TNF-α and IL-12. This leads to potentiated antitumor immune responses manifested by increased numbers of tumor-specific cytotoxic T cells, high levels of tumor cell apoptosis and delayed tumor growth. Our findings confirm the central role of A20 in controlling the immunostimulatory potency of DCs and provide a strategy for simultaneous A20 silencing and TLR activation in vivo.http://europepmc.org/articles/PMC4556692?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Floriane C M Braun Jens van den Brandt Sören Thomas Sandra Lange Juliane Schrank Claudia Gand Grzegorz K Przybylski Katrin Schmoeckel Barbara M Bröker Christian A Schmidt Piotr Grabarczyk |
spellingShingle |
Floriane C M Braun Jens van den Brandt Sören Thomas Sandra Lange Juliane Schrank Claudia Gand Grzegorz K Przybylski Katrin Schmoeckel Barbara M Bröker Christian A Schmidt Piotr Grabarczyk In Vivo Silencing of A20 via TLR9-Mediated Targeted SiRNA Delivery Potentiates Antitumor Immune Response. PLoS ONE |
author_facet |
Floriane C M Braun Jens van den Brandt Sören Thomas Sandra Lange Juliane Schrank Claudia Gand Grzegorz K Przybylski Katrin Schmoeckel Barbara M Bröker Christian A Schmidt Piotr Grabarczyk |
author_sort |
Floriane C M Braun |
title |
In Vivo Silencing of A20 via TLR9-Mediated Targeted SiRNA Delivery Potentiates Antitumor Immune Response. |
title_short |
In Vivo Silencing of A20 via TLR9-Mediated Targeted SiRNA Delivery Potentiates Antitumor Immune Response. |
title_full |
In Vivo Silencing of A20 via TLR9-Mediated Targeted SiRNA Delivery Potentiates Antitumor Immune Response. |
title_fullStr |
In Vivo Silencing of A20 via TLR9-Mediated Targeted SiRNA Delivery Potentiates Antitumor Immune Response. |
title_full_unstemmed |
In Vivo Silencing of A20 via TLR9-Mediated Targeted SiRNA Delivery Potentiates Antitumor Immune Response. |
title_sort |
in vivo silencing of a20 via tlr9-mediated targeted sirna delivery potentiates antitumor immune response. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2015-01-01 |
description |
A20 is an ubiquitin-editing enzyme that ensures the transient nature of inflammatory signaling pathways induced by cytokines like TNF-α and IL-1 or pathogens via Toll-like receptor (TLR) pathways. It has been identified as a negative regulator of dendritic cell (DC) maturation and attenuator of their immunostimulatory properties. Ex vivo A20-depleted dendritic cells showed enhanced expression of pro-inflammatory cytokines and costimulatory molecules, which resulted in hyperactivation of tumor-infiltrating T lymphocytes and inhibition of regulatory T cells. In the present study, we demonstrate that a synthetic molecule consisting of a CpG oligonucleotide TLR9 agonist linked to A20-specific siRNAs silences its expression in TLR9+ mouse dendritic cells in vitro and in vivo. In the B16 mouse melanoma tumor model, silencing of A20 enhances the CpG-triggered induction of NFκB activity followed by elevated expression of IL-6, TNF-α and IL-12. This leads to potentiated antitumor immune responses manifested by increased numbers of tumor-specific cytotoxic T cells, high levels of tumor cell apoptosis and delayed tumor growth. Our findings confirm the central role of A20 in controlling the immunostimulatory potency of DCs and provide a strategy for simultaneous A20 silencing and TLR activation in vivo. |
url |
http://europepmc.org/articles/PMC4556692?pdf=render |
work_keys_str_mv |
AT florianecmbraun invivosilencingofa20viatlr9mediatedtargetedsirnadeliverypotentiatesantitumorimmuneresponse AT jensvandenbrandt invivosilencingofa20viatlr9mediatedtargetedsirnadeliverypotentiatesantitumorimmuneresponse AT sorenthomas invivosilencingofa20viatlr9mediatedtargetedsirnadeliverypotentiatesantitumorimmuneresponse AT sandralange invivosilencingofa20viatlr9mediatedtargetedsirnadeliverypotentiatesantitumorimmuneresponse AT julianeschrank invivosilencingofa20viatlr9mediatedtargetedsirnadeliverypotentiatesantitumorimmuneresponse AT claudiagand invivosilencingofa20viatlr9mediatedtargetedsirnadeliverypotentiatesantitumorimmuneresponse AT grzegorzkprzybylski invivosilencingofa20viatlr9mediatedtargetedsirnadeliverypotentiatesantitumorimmuneresponse AT katrinschmoeckel invivosilencingofa20viatlr9mediatedtargetedsirnadeliverypotentiatesantitumorimmuneresponse AT barbarambroker invivosilencingofa20viatlr9mediatedtargetedsirnadeliverypotentiatesantitumorimmuneresponse AT christianaschmidt invivosilencingofa20viatlr9mediatedtargetedsirnadeliverypotentiatesantitumorimmuneresponse AT piotrgrabarczyk invivosilencingofa20viatlr9mediatedtargetedsirnadeliverypotentiatesantitumorimmuneresponse |
_version_ |
1725288395792449536 |