Insights into innate immune activation via PS-ASO-protein-TLR9 interactions.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
12 08 2022
12 08 2022
Historique:
accepted:
30
06
2022
revised:
14
06
2022
received:
15
12
2021
pubmed:
19
7
2022
medline:
16
8
2022
entrez:
18
7
2022
Statut:
ppublish
Résumé
Non-CpG PS-ASOs can activate the innate immune system, leading to undesired outcomes. This response can vary-in part-as a function of 2'modifications and sequence. Here we investigated the molecular steps involved in the varied effects of PS-ASOs on the innate immune system. We found that pro-inflammatory PS-ASOs require TLR9 signaling based on the experimental systems used. However, the innate immunity of PS-ASOs does not correlate with their binding affinity with TLR9. Furthermore, the innate immune responses of pro-inflammatory PS-ASOs were reduced by coincubation with non-inflammatory PS-ASOs, suggesting that both pro-inflammatory and non-inflammatory PS-ASOs can interact with TLR9. We show that the kinetics of the PS-ASO innate immune responses can vary, which we speculate may be due to the existence of alternative PS-ASO binding sites on TLR9, leading to full, partial, or no activation of the pathway. In addition, we found that several extracellular proteins, including HMGB1, S100A8 and HRG, enhance the innate immune responses of PS-ASOs. Reduction of the binding affinity by reducing the PS content of PS-ASOs decreased innate immune responses, suggesting that PS-ASO-protein complexes may be sensed by TLR9. These findings thus provide critical information concerning how PS-ASOs can interact with and activate TLR9.
Identifiants
pubmed: 35848907
pii: 6644951
doi: 10.1093/nar/gkac618
pmc: PMC9371907
doi:
Substances chimiques
Calgranulin A
0
HMGB1 Protein
0
HMGB1 protein, human
0
Oligonucleotides, Antisense
0
Phosphorothioate Oligonucleotides
0
Proteins
0
S100A8 protein, human
0
TLR9 protein, human
0
Toll-Like Receptor 9
0
histidine-rich proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
8107-8126Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.
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