Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy

Grohmann, Ursula; Volpi, Claudia; Fallarino, Francesca; Bozza, Silvia; Bianchi, Roberta; Vacca, Carmine; Orabona, Ciriana; Belladonna, Maria Laura; Ayroldi, Emira; Nocentini, Giuseppe; Boon, Louis; Bistoni, Francesco; Fioretti, Maria Cristina; Romani, Luigina; Riccardi, Carlo; Puccetti, Paolo

doi:10.1038/nm1563

Cited by 294 publications

(345 citation statements)

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“…IDO1 expression is contingent on the noncanonical pathway of NF-kB activation 19,26,27 . Molecular dissection of NF-kB activation has shown that NF-kB can be induced by the socalled canonical (classical; IkB kinase (IKK)b-dependent) and noncanonical (alternative; IKKa-dependent) signalling pathways, leading to distinct patterns in the individual NF-kB subunits that are activated and the downstream genetic responses that are induced.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2013

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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-kB signalling and the induction of IRF3-and TGF-b-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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2013

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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%

“…All purification procedures of splenic Ido1 −/− pDCs and CD8 − DCs (hereafter referred to as cDCs, for conventional DCs) were as described 7, 8, 22, 23, 24, 25. Plasmid constructs coding for WT or IDO1 mutants (Y115E, Y253E and Y115_253E, in which either one or both phosphorylable tyrosines were replaced by a glutamate residue) were used as templates for in vitro transcription of mRNA, using the mMESSAGE mMACHINE T7 Ultra Kit (Ambion, Waltham, MA USA).…”

Section: Methodsmentioning

confidence: 99%

“…A skin test assay was used for measurements of major histocompatibility complex class I‐restricted delayed‐type hypersensitivity (DTH) responses to the HY peptide 8, 25 in C57BL/6 female recipient mice. For in vivo immunization, 3 × 10 5 peptide‐loaded cDCs, combined with a minority fraction (5%) of peptide‐loaded transfected Ido1 −/− pDCs, were injected subcutaneously into recipient mice.…”

Section: Methodsmentioning

confidence: 99%

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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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“…This is similar to the situation in AA: These individuals do have considerable specific blood IgE levels against common aeroallergens (51), although the IDO pathway seems to be active during allergen exposure. In a mouse model, it has recently been shown how IDO can mediate a glucocorticoid-dependent anti-inflammatory effect in allergic bronchopulmonary aspergillosis (ABPA) (52). Engagement of the glucocorticoid-induced tumor necrosis factor receptor ligand (GITRL) on pDCs by soluble GITR has been found to initiate trp catabolism by inducing IDO in pDCs.…”

Section: Ido and The Ido Pathway Control Allergic Inflammationmentioning

confidence: 99%

The indoleamine 2,3‐dioxygenase (IDO) pathway controls allergy

Bubnoff

Bieber

2012

Allergy

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A series of recent studies have demonstrated that the immunoregulatory pathway of tryptophan catabolism, initiated by the enzyme indoleamine 2,3-dioxygenase (IDO), is a critical participant in allergic inflammation. Originally known for its regulatory function during pregnancy and during chronic inflammation in tumorigenesis and infection, the activity of IDO seems to positively modify the inflammatory state of atopy or allergy. The tryptophan degradation pathway is important for tolerance induction during systemic allergen immunotherapy. Here, we focus on recent findings that establish the IDO pathway as central to allergic inflammation.The indoleamine 2,3-dioxygenase (IDO) pathway has been found to contribute substantially to the control of allergic inflammation. Traditionally recognized for its immunomodulatory role in infection, pregnancy, autoimmunity, and neoplasia, the effect of IDO on allergy appears to be a another piece of puzzle in the 'hygiene hypothesis'. Early microbial exposure and thus the stimulation of the IDO pathway by distinct Toll-like receptors (TLR) may, together with other immunoregulatory pathways, shape the predisposition to and determine the outcome of allergic inflammation, autoimmunity, and probably other diseases. Current data suggest that a normal induction of IDO activity, which decreases serum tryptophan (trp) levels and increases the levels of trp metabolites, controls the allergic inflammation. The mechanism of IDO-induced tolerance induction can probably be manifold but the induction of regulatory T cells may be a major aspect of the control function over allergic inflammation. This review summarizes the current knowledge on the IDO pathway and its role in regulating immune functions with a focus on allergic diseases.Tryptophan and its degradation pathways: indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase (TDO)As an essential amino acid, tryptophan (trp) is a constituent of proteins. Inadequate dietary intake of trp and other essential amino acids can lead to a negative nitrogen balance and to a loss of muscle mass, brain size, and weight (1). Trp is an essential starting point of two biochemical pathways: (i) the enzyme tryptophan 5-hydroxylase converts trp into 5-hydroxytryptophan, which is subsequently decarboxylized to 5-hydroxytryptamine (5-HT, serotonin), an essential neurotransmitter and vasoconstrictor, and (ii) two atoms of the molecular oxygen are inserted into L-trp to form N-formylkynurenine, the first and rate-limiting step in the kynurenine pathway (Fig. 1) (2, 3). The activation of molecular oxygen and its insertion into trp are catalyzed by three

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Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy

Cited by 294 publications

References 50 publications

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

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

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

The indoleamine 2,3‐dioxygenase (IDO) pathway controls allergy

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