The proprotein convertase PC1/3 regulates TLR9 trafficking and the associated signaling pathways

Endosomal TLR9 is considered as a potent anti-tumoral therapeutic target. Therefore, it is crucial to decipher the mechanisms controlling its trafficking since it determines TLR9 activation and signalling. At present, the scarcity of molecular information regarding the control of this trafficking an...

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Bibliographic Details
Published in:Scientific reports 2016-01, Vol.6 (1), p.19360-19360, Article 19360
Main Authors: Duhamel, M, Rodet, F, Murgoci, A N, Desjardins, R, Gagnon, H, Wisztorski, M, Fournier, I, Day, R, Salzet, M
Format: Article
Language:English
Subjects:
Animals
Cytokines - biosynthesis
Endosomes
Endosomes - metabolism
Enzyme Activation - drug effects
Inflammation
Interleukin 1
Interleukin 6
Life Sciences
Localization
Macrophages
Macrophages, Alveolar - metabolism
Macrophages, Peritoneal - metabolism
Mice
Mice, Knockout
Mice, Transgenic
MyD88 protein
NF-kappa B - metabolism
NF-κB protein
Oligodeoxyribonucleotides - immunology
Oligodeoxyribonucleotides - pharmacology
Oligonucleotides
pH effects
Proprotein Convertase 1 - metabolism
Proprotein convertases
Protein Binding
Protein Transport
Proteolysis - drug effects
Rats
Rodents
Signal Transduction
Stat3 protein
STAT3 Transcription Factor - metabolism
TLR4 protein
TLR9 protein
Toll-Like Receptor 9 - metabolism
Toll-like receptors
Tumor necrosis factor
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Summary:Endosomal TLR9 is considered as a potent anti-tumoral therapeutic target. Therefore, it is crucial to decipher the mechanisms controlling its trafficking since it determines TLR9 activation and signalling. At present, the scarcity of molecular information regarding the control of this trafficking and signalling is noticeable. We have recently demonstrated that in macrophages, proprotein convertase 1/3 (PC1/3) is a key regulator of TLR4 Myd88-dependent signalling. In the present study, we established that PC1/3 also regulates the endosomal TLR9. Under CpG-ODN challenge, we found that PC1/3 traffics rapidly to co-localize with TLR9 in CpG-ODN-containing endosomes with acidic pH. In PC1/3 knockdown macrophages, compartmentalization of TLR9 was altered and TLR9 clustered in multivesicular bodies (MVB) as demonstrated by co-localization with Rab7. This demonstrates that PC1/3 controls TLR9 trafficking. This clustering of TLR9 in MVB dampened the anti-inflammatory STAT3 signalling pathway while it promoted the pro-inflammatory NF-kB pathway. As a result, macrophages from PC1/3 KO mice and rat PC1/3-KD NR8383 macrophages secreted more pro-inflammatory cytokines such as TNF-α, IL6, IL1α and CXCL2. This is indicative of a M1 pro-inflammatory phenotype. Therefore, PC1/3 KD macrophages represent a relevant mean for cell therapy as "Trojan" macrophages.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep19360