LPS-conditioned dendritic cells confer endotoxin tolerance contingent on tryptophan catabolism

Fallarino, Francesca; Pallotta, Maria Teresa; Matino, Davide; Gargaro, Marco; Orabona, Ciriana; Vacca, Carmine; Mondanelli, Giada; Allegrucci, M.; Boon, Louis; Romani, Rita; Talesa, Vincenzo Nicola; Puccetti, Paolo; Grohmann, Ursula

doi:10.1016/j.imbio.2014.09.017

Cited by 34 publications

(39 citation statements)

References 35 publications

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“…In accordance with this, a recent study has demonstrated that single exposure of murine conventional DCs (cDCs) to LPS elicits pro-inflammatory IL-6, but not IDO1 expression, whereas consecutive exposure of these cells to LPS up-regulates both IDO1 and TGFβ [483]. Only cDCs receiving consecutive exposure to LPS conferred in vivo protection in mice treated with a lethal LPS dose [483].…”

Section: Micro-organism Induction Of Ido1 In Vivomentioning

confidence: 80%

Role of indoleamine 2,3-dioxygenase in health and disease

et al. 2015

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IDO1 (indoleamine 2,3-dioxygenase 1) is a member of a unique class of mammalian haem dioxygenases that catalyse the oxidative catabolism of the least-abundant essential amino acid, L-Trp (L-tryptophan), along the kynurenine pathway. Significant increases in knowledge have been recently gained with respect to understanding the fundamental biochemistry of IDO1 including its catalytic reaction mechanism, the scope of enzyme reactions it catalyses, the biochemical mechanisms controlling IDO1 expression and enzyme activity, and the discovery of enzyme inhibitors. Major advances in understanding the roles of IDO1 in physiology and disease have also been realised. IDO1 is recognised as a prominent immune regulatory enzyme capable of modulating immune cell activation status and phenotype via several molecular mechanisms including enzyme-dependent deprivation of L-Trp and its conversion into the aryl hydrocarbon receptor ligand kynurenine and other bioactive kynurenine pathway metabolites, or non-enzymatic cell signalling actions involving tyrosine phosphorylation of IDO1. Through these different modes of biochemical signalling, IDO1 regulates certain physiological functions (e.g. pregnancy) and modulates the pathogenesis and severity of diverse conditions including chronic inflammation, infectious disease, allergic and autoimmune disorders, transplantation, neuropathology and cancer. In the present review, we detail the current understanding of IDO1's catalytic actions and the biochemical mechanisms regulating IDO1 expression and activity. We also discuss the biological functions of IDO1 with a focus on the enzyme's immune-modulatory function, its medical implications in diverse pathological settings and its utility as a therapeutic target.

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Section: Micro-organism Induction Of Ido1 In Vivomentioning

confidence: 80%

Role of indoleamine 2,3-dioxygenase in health and disease

et al. 2015

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“…However, there is evidence that activation of TLR4 can generate pro-tolerance as well as inflammatory responses to limit damage during inflammation [65]. Indeed TLR4 has been suggested to act directly or indirectly to induce the differentiation, activation and proliferation of Treg cells [66][67][68]. In mice, CD45RB low CD25 + regulatory T cells, which function to control inflammatory responses to commensal bacteria and pathogens, selectively express TLR4 and enhance their suppressive function following exposure to LPS [66].…”

Section: Discussionmentioning

confidence: 99%

TLR4 Signaling Is a Major Mediator of the Female Tract Response to Seminal Fluid in Mice1

Schjenken

Glynn

Sharkey

et al. 2015

Biology of Reproduction

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Seminal fluid interacts with epithelial cells lining the female reproductive tract to induce expression of proinflammatory cytokines and chemokines, initiating immune tolerance mechanisms to facilitate pregnancy. TGFB cytokines are key signaling agents in seminal plasma but do not fully account for the female response to seminal fluid. We hypothesized that additional molecular pathways are utilized in seminal fluid signaling. Affymetrix microarray was employed to compare gene expression in the endometrium of mice 8 h after mating with either intact males or seminal fluid deficient (SVX/VAS) males. Bioinformatics analysis revealed TLR4 signaling as a strongly predicted upstream regulator activated by the differentially expressed genes and implicated TGFB signaling as a second key pathway. Quantitative PCR and microbead data confirmed that seminal fluid induces endometrial synthesis of several TLR4-regulated cytokines and chemokines, including CSF3, CXCL1, CXCL2, IL1A, IL6, LIF, and TNF. In primary uterine epithelial cells, CSF3, CXCL1, and CXCL2 were strongly induced by the TLR4 ligand LPS but suppressed by TGFB, while IL1A, TNF, and CSF2 were induced by both ligands. TLR4 was confirmed as essential for the full endometrial cytokine response using mice with a null mutation in Tlr4, where seminal fluid failed to induce endometrial Csf3, Cxcl2, Il6, and Tnf expression. This study provides evidence that TLR4 contributes to seminal fluid modulation of the periconception immune environment. Activation of TLR4 signaling by microbial or endogenous components of seminal fluid is thus implicated as a key element of the female tract response to seminal fluid at the outset of pregnancy in mice.

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“…In line with the functions of seminal fl uid, activation of TLR4 signalling may contribute to tolerogenic immune responses (Conroy et al 2008 ), as studies have demonstrated that CD45RB low CD25 + regulatory T cells can express TLR4 and enhance suppressive function following TLR4 ligation (Caramalho et al 2003 ), dendritic cells from TLR4-defi cient mice have reduced capacity to produce IL10 in response to TLR4 ligation and have impaired expansion of Treg cells (Higgins et al 2003 ), and Treg cells cultured in the presence of dendritic cells can induce tryptophan catabolism which enhances tolerogenic dendritic cell production (Fallarino et al 2015 ). More detailed studies are required to understand how disruption of TLR4 signalling may affect the female response to seminal fl uid in the mouse and other species and how in turn offspring health might be affected.…”

Section: Active Factors In Seminal Fluidmentioning

confidence: 99%

Seminal Fluid Signalling in the Female Reproductive Tract: Implications for Reproductive Success and Offspring Health

Schjenken

Robertson

2015

Advances in Experimental Medicine and Biology

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Carriage of sperm is not the only function of seminal fluid in mammals. Studies in mice show that at conception, seminal fluid interacts with the female reproductive tract to induce responses which influence whether or not pregnancy will occur, and to set in train effects that help shape subsequent fetal development. In particular, seminal fluid initiates female immune adaptation processes required to tolerate male transplantation antigens present in seminal fluid and inherited by the conceptus. A tolerogenic immune environment to facilitate pregnancy depends on regulatory T cells (Treg cells), which recognise male antigens and function to suppress inflammation and immune rejection responses. The female response to seminal fluid stimulates the generation of Treg cells that protect the conceptus from inflammatory damage, to support implantation and placental development. Seminal fluid also elicits molecular and cellular changes in the oviduct and endometrium that directly promote embryo development and implantation competence. The plasma fraction of seminal fluid plays a key role in this process with soluble factors, including TGFB, prostaglandin-E, and TLR4 ligands, demonstrated to contribute to the peri-conception immune environment. Recent studies show that conception in the absence of seminal plasma in mice impairs embryo development and alters fetal development to impact the phenotype of offspring, with adverse effects on adult metabolic function particularly in males. This review summarises our current understanding of the molecular responses to seminal fluid and how this contributes to the establishment of pregnancy, generation of an immune-regulatory environment and programming long-term offspring health.

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LPS-conditioned dendritic cells confer endotoxin tolerance contingent on tryptophan catabolism

Cited by 34 publications

References 35 publications

Role of indoleamine 2,3-dioxygenase in health and disease

Role of indoleamine 2,3-dioxygenase in health and disease

TLR4 Signaling Is a Major Mediator of the Female Tract Response to Seminal Fluid in Mice1

Seminal Fluid Signalling in the Female Reproductive Tract: Implications for Reproductive Success and Offspring Health

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