CpG-rich oligodeoxynucleotides activate the immune system, leading to innate and acquired immune responses. The immune-stimulatory effects of CpG-rich oligodeoxynucleotides are being exploited as a therapeutic approach. Here we show that at high doses, CpG-rich oligodeoxynucleotides promote an opposite, tolerogenic response in mouse plasmacytoid dendritic cells in vivo and in a human in vitro model. Unveiling a previously undescribed role for TRIF and TRAF6 proteins in Toll-like receptor 9 (TLR9) signalling, we demonstrate that physical association of TLR9, TRIF and TRAF6 leads to activation of noncanonical NF-κB signalling and the induction of IRF3- and TGF-β-dependent immune-suppressive tryptophan catabolism. In vivo, the TLR9-TRIF circuit--but not MyD88 signalling--was required for CpG protection against allergic inflammation. Our findings may be relevant to an increased understanding of the complexity of Toll-like receptor signalling and optimal exploitation of CpG-rich oligodeoxynucleotides as immune modulators.

High doses of CpG oligodeoxynucleotides stimulate a tolerogenic TLR9-TRIF pathway.

VOLPI, CLAUDIA;FALLARINO, Francesca;PALLOTTA, MARIA TERESA;BIANCHI, Roberta;VACCA, Carmine;BELLADONNA, Maria Laura;ORABONA, Ciriana;DE LUCA, ANTONELLA;ROMANI, Luigina;GROHMANN, Ursula;PUCCETTI, Paolo
2013

Abstract

CpG-rich oligodeoxynucleotides activate the immune system, leading to innate and acquired immune responses. The immune-stimulatory effects of CpG-rich oligodeoxynucleotides are being exploited as a therapeutic approach. Here we show that at high doses, CpG-rich oligodeoxynucleotides promote an opposite, tolerogenic response in mouse plasmacytoid dendritic cells in vivo and in a human in vitro model. Unveiling a previously undescribed role for TRIF and TRAF6 proteins in Toll-like receptor 9 (TLR9) signalling, we demonstrate that physical association of TLR9, TRIF and TRAF6 leads to activation of noncanonical NF-κB signalling and the induction of IRF3- and TGF-β-dependent immune-suppressive tryptophan catabolism. In vivo, the TLR9-TRIF circuit--but not MyD88 signalling--was required for CpG protection against allergic inflammation. Our findings may be relevant to an increased understanding of the complexity of Toll-like receptor signalling and optimal exploitation of CpG-rich oligodeoxynucleotides as immune modulators.
2013
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11391/1111466
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