title: The proprotein convertase PC1/3 regulates TLR9 trafficking and the associated signaling pathways.
abstract: 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.
authors.affiliation: Univ. Lille, INSERM, U1192 - Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse-PRISM, F-59000 Lille, France.
authors.forename: M
authors.initials: M
authors.lastname: Duhamel
authors.affiliation: Univ. Lille, INSERM, U1192 - Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse-PRISM, F-59000 Lille, France.
authors.forename: F
authors.initials: F
authors.lastname: Rodet
authors.affiliation: Univ. Lille, INSERM, U1192 - Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse-PRISM, F-59000 Lille, France.
authors.forename: A N
authors.initials: AN
authors.lastname: Murgoci
authors.affiliation: Institut de Pharmacologie, Département de Chirurgie/Service d'Urologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, 3001 12e Ave Nord, Sherbrooke, Qc, Canada, J1H 5N4.
authors.forename: R
authors.initials: R
authors.lastname: Desjardins
authors.affiliation: Institut de Pharmacologie, Département de Chirurgie/Service d'Urologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, 3001 12e Ave Nord, Sherbrooke, Qc, Canada, J1H 5N4.
authors.forename: H
authors.initials: H
authors.lastname: Gagnon
authors.affiliation: Univ. Lille, INSERM, U1192 - Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse-PRISM, F-59000 Lille, France.
authors.forename: M
authors.initials: M
authors.lastname: Wisztorski
authors.affiliation: Univ. Lille, INSERM, U1192 - Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse-PRISM, F-59000 Lille, France.
authors.forename: I
authors.initials: I
authors.lastname: Fournier
authors.affiliation: Institut de Pharmacologie, Département de Chirurgie/Service d'Urologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, 3001 12e Ave Nord, Sherbrooke, Qc, Canada, J1H 5N4.
authors.forename: R
authors.initials: R
authors.lastname: Day
authors.affiliation: Univ. Lille, INSERM, U1192 - Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse-PRISM, F-59000 Lille, France.
authors.forename: M
authors.initials: M
authors.lastname: Salzet
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D011992:Endosomes / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology; D045664:Proprotein Convertase 1 / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
chemical_list: C408982:CPG-oligonucleotide; D016207:Cytokines; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D050796:STAT3 Transcription Factor; D051217:Toll-Like Receptor 9; D045664:Proprotein Convertase 1