Blockade of Indoleamine 2,3-Dioxygenase Reduces Mortality from Peritonitis and Sepsis in Mice by Regulating Functions of CD11b<sup>+</sup>Peritoneal Cells

Hoshi, Masato; Osawa, Yosuke; Ito, Hiroyasu; Ohtaki, Hirofumi; Ando, Tatsuya; Takamatsu, Manabu; Hara, Akira; Seishima, Mitsuru

doi:10.1128/iai.02113-14

Cited by 35 publications

(35 citation statements)

References 54 publications

(63 reference statements)

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“…This decrease correlated with higher disease severity as measured by higher levels of PCT Brought to you by | Universitaetsbibliothek Basel Authenticated Download Date | 10/9/17 4:17 PM and CRP, and higher risk scores (qSOFA and PSI). These results are in line with previous research [26][27][28]. The physiopathological mechanism of decreasing TRP during infection and inflammation is a matter of current discussion [29].…”

Section: Discussionsupporting

confidence: 82%

“…In a mouse model, IDO inhibitors potentiated cancer chemotherapy because of an immune-modulating effect of IDO [32]. Also, a blockade of IDO showed a reduction in mortality from peritonitis and sepsis in mice [27]. Despite these promising early results, clinical data is currently lacking demonstrating whether an IDO inhibitor could improve patient outcome in acute infection and sepsis.…”

Section: Discussionmentioning

confidence: 97%

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Activation of the tryptophan/serotonin pathway is associated with severity and predicts outcomes in pneumonia: results of a long-term cohort study

Meier

Ottiger

Vögeli

et al. 2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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Background: As part of the immune defense during infection, an increase in enzyme activity of indoleamine 2,3-dioxygenase (IDO) leads to a breakdown of tryptophan to kynurenine. In previous animal studies, therapeutic antagonism of IDO resulted in reduced sepsis mortality. We investigated the prognostic ability of tryptophan, serotonin, kynurenine and IDO (represented by the ratio of kynurenine/tryptophan) to predict adverse clinical outcomes in patients with community-acquired pneumonia (CAP). Methods: We measured tryptophan, serotonin and kynurenine on admission plasma samples from CAP patients included in a previous multicenter trial by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). We studied their association with inflammation (C-reactive protein), infection (procalcitonin) and clinical outcome. Results: Mortality in the 268 included patients was 45% within 6 years of follow-up. IDO and kynurenine showed a

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 97%

Activation of the tryptophan/serotonin pathway is associated with severity and predicts outcomes in pneumonia: results of a long-term cohort study

Meier

Ottiger

Vögeli

et al. 2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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“…Clinical and experimental animal studies highlight an important role for IDO1 and the Kyn pathway in response to endotoxic shock. IDO1 expression and activity are increased in septic patients and animals in inflamed cardiac tissue, spleen DCs, bone marrow-derived CD11b + cells and endothelial cells of resistance vessels [125,182,479,480]. Moreover, IDO1 activity measured as the plasma Kyn/L-Trp ratio is significantly elevated in patients with bacteraemia caused by S. aureus, S. pneumoniae, E. coli and β-haemolytic streptococci, with the extent of increase representing an independent predictor of disease severity and death [481,482].…”

Section: Micro-organism Induction Of Ido1 In Vivomentioning

confidence: 95%

“…A more recent study reported that IDO1 gene deficiency or 1-D-MT treatment also afforded host protection and reduced mortality in mouse models of bacterial peritonitis or sepsis after caecal ligation and puncture, involving elevated chemokine expression and enhanced recruitment of neutrophils and mononuclear cells into the peritoneum, which correlated with reduced bacterial load [480]. The septic phenotype apparent in wild-type mice was also recapitulated in IDO1 −/− mice treated with Kyn or reconstituted with IDO1 +/+ bone marrow cells, suggesting that Kyn produced by IDO1-expressing leucocytes plays an important role in promoting sepsis [480]. These studies identify a deleterious proinflammatory action for IDO1 during sepsis.…”

Section: Micro-organism Induction Of Ido1 In Vivomentioning

confidence: 97%

“…M. tuberculosis) or, in the case of Chlamydia, respond to IDO1 by transitioning into a viable and persistent form that may further exacerbate the degree of inflammation. Furthermore, there is evidence for important roles for IDO1's immunomodulatory action in bacterial infection, particularly during sepsis, where IDO1 can elicit both beneficial immunosuppressive [25] or deleterious pro-inflammatory [125,259,480] actions. Overall, although it is clear that IDO1 plays a significant role in several clinically relevant bacterial infections or syndromes, including tuberculosis and sepsis, the bulk of the data is either from in vitro cell studies or in vivo mouse models.…”

Section: Micro-organism Induction Of Ido1 In Vivomentioning

confidence: 98%

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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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Orchestration of Tryptophan‐Kynurenine Pathway, Acute Decompensation, and Acute‐on‐Chronic Liver Failure in Cirrhosis

et al. 2019

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Systemic inflammation (SI) is involved in the pathogenesis of acute decompensation (AD) and acute‐on‐chronic liver failure (ACLF) in cirrhosis. In other diseases, SI activates tryptophan (Trp) degradation through the kynurenine pathway (KP), giving rise to metabolites that contribute to multiorgan/system damage and immunosuppression. In the current study, we aimed to characterize the KP in patients with cirrhosis, in whom this pathway is poorly known. The serum levels of Trp, key KP metabolites (kynurenine and kynurenic and quinolinic acids), and cytokines (SI markers) were measured at enrollment in 40 healthy subjects, 39 patients with compensated cirrhosis, 342 with AD (no ACLF) and 180 with ACLF, and repeated in 258 patients during the 28‐day follow‐up. Urine KP metabolites were measured in 50 patients with ACLF. Serum KP activity was normal in compensated cirrhosis, increased in AD and further increased in ACLF, in parallel with SI; it was remarkably higher in ACLF with kidney failure than in ACLF without kidney failure in the absence of differences in urine KP activity and fractional excretion of KP metabolites. The short‐term course of AD and ACLF (worsening, improvement, stable) correlated closely with follow‐up changes in serum KP activity. Among patients with AD at enrollment, those with the highest baseline KP activity developed ACLF during follow‐up. Among patients who had ACLF at enrollment, those with immune suppression and the highest KP activity, both at baseline, developed nosocomial infections during follow‐up. Finally, higher baseline KP activity independently predicted mortality in patients with AD and ACLF. Conclusion: Features of KP activation appear in patients with AD, culminate in patients with ACLF, and may be involved in the pathogenesis of ACLF, clinical course, and mortality.

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Blockade of Indoleamine 2,3-Dioxygenase Reduces Mortality from Peritonitis and Sepsis in Mice by Regulating Functions of CD11b⁺Peritoneal Cells

Cited by 35 publications

References 54 publications

Activation of the tryptophan/serotonin pathway is associated with severity and predicts outcomes in pneumonia: results of a long-term cohort study

Activation of the tryptophan/serotonin pathway is associated with severity and predicts outcomes in pneumonia: results of a long-term cohort study

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

Orchestration of Tryptophan‐Kynurenine Pathway, Acute Decompensation, and Acute‐on‐Chronic Liver Failure in Cirrhosis

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Blockade of Indoleamine 2,3-Dioxygenase Reduces Mortality from Peritonitis and Sepsis in Mice by Regulating Functions of CD11b+Peritoneal Cells

Cited by 35 publications

References 54 publications

Activation of the tryptophan/serotonin pathway is associated with severity and predicts outcomes in pneumonia: results of a long-term cohort study

Activation of the tryptophan/serotonin pathway is associated with severity and predicts outcomes in pneumonia: results of a long-term cohort study

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

Orchestration of Tryptophan‐Kynurenine Pathway, Acute Decompensation, and Acute‐on‐Chronic Liver Failure in Cirrhosis

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Blockade of Indoleamine 2,3-Dioxygenase Reduces Mortality from Peritonitis and Sepsis in Mice by Regulating Functions of CD11b⁺Peritoneal Cells