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; Luca, Antonella De; Boon, Louis; Romani, Luigina; Grohmann, Ursula; Puccetti, Paolo

doi:10.1038/ncomms2874

Cited by 103 publications

(112 citation statements)

References 48 publications

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“…Specifically, the ITIM‐mediated IDO1 plasticity would translate in DCs into opposite functional phenotypes, that is , immunoadjuvant versus immunoregulatory in nature 9. In this regard, it should be noted that pDCs represent the most flexible DC subset, capable of rapidly shifting from an immunostimulatory to an immunosuppressive programme and vice versa in response to inflammatory versus anti‐inflammatory signals 25, 37. The inflammatory versus anti‐inflammatory milieu sensed by pDC may promote not only a differential expression of the IDO1's molecular partner ( i.e .…”

Section: Discussionmentioning

confidence: 99%

Distinct roles of immunoreceptor tyrosine‐based motifs in immunosuppressive indoleamine 2,3‐dioxygenase 1

Albini

Rosini

Gargaro

et al. 2016

J Cellular Molecular Medi

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The enzyme indoleamine 2,3‐dioxygenase 1 (IDO1) catalyses the initial, rate‐limiting step in tryptophan (Trp) degradation, resulting in tryptophan starvation and the production of immunoregulatory kynurenines. IDO1's catalytic function has long been considered as the one mechanism responsible for IDO1‐dependent immune suppression by dendritic cells (DCs), which are master regulators of the balance between immunity and tolerance. However, IDO1 also harbours immunoreceptor tyrosine‐based inhibitory motifs, (ITIM1 and ITIM2), that, once phosphorylated, bind protein tyrosine phosphatases, (SHP‐1 and SHP‐2), and thus trigger an immunoregulatory signalling in DCs. This mechanism leads to sustained IDO1 expression, in a feedforward loop, which is particularly important in restraining autoimmunity and chronic inflammation. Yet, under specific conditions requiring that early and protective inflammation be unrelieved, tyrosine‐phosphorylated ITIMs will instead bind the suppressor of cytokine signalling 3 (SOCS3), which drives IDO1 proteasomal degradation and shortens the enzyme half‐life. To dissect any differential roles of the two IDO1's ITIMs, we generated protein mutants by replacing one or both ITIM‐associated tyrosines with phospho‐mimicking glutamic acid residues. Although all mutants lost their enzymic activity, the ITIM1 – but not ITIM2 mutant – did bind SHPs and conferred immunosuppressive effects on DCs, making cells capable of restraining an antigen‐specific response in vivo. Conversely, the ITIM2 mutant would preferentially bind SOCS3, and IDO1's degradation was accelerated. Thus, it is the selective phosphorylation of either ITIM that controls the duration of IDO1 expression and function, in that it dictates whether enhanced tolerogenic signalling or shutdown of IDO1‐dependent events will occur in a local microenvironment.

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Section: Discussionmentioning

confidence: 99%

Distinct roles of immunoreceptor tyrosine‐based motifs in immunosuppressive indoleamine 2,3‐dioxygenase 1

Albini

Rosini

Gargaro

et al. 2016

J Cellular Molecular Medi

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“…This may be due to that TLRs act as the host's first line of defense against invading pathogens and aeroallergens, making them be involved in the pathophysiology of allergic airway diseases such as asthma (Duechs et al, 2011;Aryan et al, 2014). Until now, TLR9 has been reported to be abundantly expressed in cells including eosinophils, mast cells, plasmacytoid DCs and epithelial cells, and has been widely studied in asthma (Adner et al, 2013;Ramaprakash and Hogaboam, 2010;Volpi et al, 2013).…”

Section: Introductionmentioning

confidence: 96%

SP600125 promotes resolution of allergic airway inflammation via TLR9 in an OVA-induced murine acute asthma model

Fang

Shen

et al. 2015

Molecular Immunology

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“…Furthermore, recent studies indicate that high concentrations of CpG oligodeoxynucleotides stimulate a tolerogenic TLR9-TIR domain containing adapter inducing interferon-β (TRIF) pathway in pDCs; such DCs, for example, prevent airways inflammation. 44,45 It is possible that such a pathway is also stimulated in atherosclerotic lesions. Unfortunately, there is no specific surface marker that would allow the identification of tolerogenic DCs in atherosclerotic plaques.…”

Section: With Odn 1668mentioning

confidence: 99%

Protective Role for Toll-Like Receptor-9 in the Development of Atherosclerosis in Apolipoprotein E–Deficient Mice

Koulis

Chen

Hausding

et al. 2014

ATVB

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Objective— Atherosclerosis is driven by inflammatory reactions that are shared with the innate immune system. Toll-like receptor-9 (TLR9) is an intracellular pattern recognition receptor of the innate immune system that is currently under clinical investigation as a therapeutic target in inflammatory diseases. Here, we investigated whether TLR9 has a role in the development of atherosclerosis in apolipoprotein E–deficient (ApoE −/− ) mice. Approach and Results— Newly generated double-knockout ApoE −/− :TLR9 −/− mice and control ApoE −/− mice were fed a high-fat diet from 8 weeks and effects on lesion size, cellular composition, inflammatory status, and plasma lipids were assessed after 8, 12, 15, and 20 weeks. All 4 time points demonstrated exacerbated atherosclerotic lesion severity in ApoE −/− :TLR9 −/− mice, with a corresponding increase in lipid deposition and accumulation of macrophages, dendritic cells, and CD4 + T cells. Although ApoE −/− :TLR9 −/− mice exhibited an increase in plasma very low-density lipoprotein/low-density-lipoprotein cholesterol, the very low-density lipoprotein/low-density lipoprotein:high-density lipoprotein ratio was unaltered because of a parallel increase in plasma high-density lipoprotein cholesterol. As a potential mechanism accounting for plaque progression in ApoE −/− :TLR9 −/− mice, CD4 + T-cell accumulation was further investigated and depletion of these cells in ApoE −/− :TLR9 −/− mice significantly reduced lesion severity. As a final translational approach, administration of a TLR9 agonist (type B CpG oligodeoxynucleotide 1668) to ApoE −/− mice resulted in a reduction of lesion severity. Conclusions— Genetic deletion of the innate immune receptor TLR9 exacerbated atherosclerosis in ApoE −/− mice fed a high-fat diet. CD4 + T cells were identified as potential mediators of this effect. A type B CpG oligodeoxynucleotide TLR9 agonist reduced lesion severity, thus identifying a novel therapeutic approach in atherosclerosis.

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High doses of CpG oligodeoxynucleotides stimulate a tolerogenic TLR9–TRIF pathway

Cited by 103 publications

References 48 publications

Distinct roles of immunoreceptor tyrosine‐based motifs in immunosuppressive indoleamine 2,3‐dioxygenase 1

Distinct roles of immunoreceptor tyrosine‐based motifs in immunosuppressive indoleamine 2,3‐dioxygenase 1

SP600125 promotes resolution of allergic airway inflammation via TLR9 in an OVA-induced murine acute asthma model

Protective Role for Toll-Like Receptor-9 in the Development of Atherosclerosis in Apolipoprotein E–Deficient Mice

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