Tryptophan-kynurenine pathway is dysregulated in inflammation and immune activation

Wang, Qiongxin; Liu, Danxia; Song, Ping; Zou, Ming

doi:10.2741/4363

Cited by 281 publications

(70 citation statements)

References 213 publications

(335 reference statements)

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“…To identify Kyn pathway catabolites that upregulate MMP2, the expression and activity of MMP2 were detected in HASMCs incubated with major exogenous metabolites 6, 37 of Trp degradation. A dramatic increase in MMP2 expression and activity was observed with 3-HAA, 38–41 but not with Kyn, 10 3-HK, 10 kynurenic acid (KA), 42 AA, 43 xanthurenic acid (XA), 44 or quinolinic acid (QA) 45 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In other cell types, Trp is catalyzed by an alternative inducible indoleamine-pyrrole 2,3-dioxygenase (IDO) under certain pathophysiological conditions. 6 The first stable intermediate from the Kyn pathway is Kyn. Subsequently, in eukaryotes, kynureninase (KNU) directly catalyzes the hydrolysis of Kyn or 3-hydroxykynurenine (3-HK) to form anthranilic acid (AA) or 3-hydroxyanthranilic acid (3-HAA), respectively.…”

Section: Introductionmentioning

confidence: 99%

“…7, 8 Catabolites in the Kyn pathway of Trp metabolism play critical roles in vascular physiology and pathology 9, 10 in addition to regulating the immune system 11, 12 and inflammation. 6, 13 Moreover, IDO is a potential novel contributor to vessel relaxation in systemic infections, 1415 which are also activated in acute severe heart attacks. 16 Recently, IDO was reported to play a critical role in atherogenesis in mice.…”

Section: Introductionmentioning

confidence: 99%

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Tryptophan-Derived 3-Hydroxyanthranilic Acid Contributes to Angiotensin II–Induced Abdominal Aortic Aneurysm Formation in Mice In Vivo

Wang¹,

Ding²,

Song³

et al. 2017

Circulation

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Background Abnormal amino acid metabolism is associated with vascular disease. However, the causative link between dysregulated tryptophan metabolism and abdominal aortic aneurysm (AAA) is unknown. Methods Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme in the kynurenine pathway of tryptophan metabolism. Mice with deficiencies in both apolipoprotein e (Apoe) and IDO (Apoe−/−/IDO−/−) were generated by cross-breeding IDO−/− mice with Apoe−/− mice. Results The acute infusion of angiotensin II (AngII) markedly increased the incidence of AAA in Apoe−/− mice, but not in Apoe−/−/IDO−/− mice, which presented decreased elastic lamina degradation and aortic expansion. These features were not altered by the reconstitution of bone marrow cells from IDO+/+ mice. Moreover, AngII infusion instigated interferon (IFN)-γ, which induced the expression of IDO and kynureninase (KNU) and increased 3-hydroxyanthranilic acid (3-HAA) levels in the plasma and aortas of Apoe−/− mice, but not in IDO−/− mice. Both IDO and KNU controlled the production of 3-HAA in vascular smooth muscle cells. 3-HAA upregulated MMP2 via transcription factor nuclear factor-kappa B (NF-κB). Furthermore, KNU knockdown in mice restrained 3-HAA, matrix metallopeptidase (MMP)2, and resultant AAA formation by AngII infusion. Intra-peritoneal injections of 3-HAA into Apoe−/− and Apoe−/−/IDO−/− mice for 6 weeks increased the expression and activity of MMP2 in aortas without affecting metabolic parameters. Finally, human AAA samples had stronger staining with the antibodies against 3-HAA, IDO, and KNU than those in adjacent nonaneurysmal aortic sections of human AAA samples. Conclusions These data define a previously undescribed causative role for 3-HAA, which is a product of tryptophan metabolism, in AAA formation. Furthermore, these findings suggest that 3-HAA reduction may be a new target for treating cardiovascular diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tryptophan-Derived 3-Hydroxyanthranilic Acid Contributes to Angiotensin II–Induced Abdominal Aortic Aneurysm Formation in Mice In Vivo

Wang¹,

Ding²,

Song³

et al. 2017

Circulation

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“…Given the multifaceted contribution of the kynurenine pathway in fundamental biological processes, impacting on inflammation, oxidative stress, and endothelial function, current literature suggests an involvement of kynurenine in both acute and chronic kidney disease [18, 28]. Previous studies have demonstrated that metabolites of the kynurenine pathway are elevated in CKD animal models as well as in CKD patients [21, 29], and kynurenine metabolites were shown to increase parallely to decreasing renal function [29, 30].…”

Section: Discussionmentioning

confidence: 99%

Pre-Interventional Kynurenine Predicts Medium-Term Outcome after Contrast Media Exposure Due to Coronary Angiography

Reichetzeder

Heunisch

Einem

et al. 2017

Kidney Blood Press Res

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Background/Aims: Contrast induced acute kidney injury (CI-AKI) remains a serious complication of contrast media enhanced procedures like coronary angiography. There is still a lack of established biomarkers that help to identify patients at high risk for short and long-term complications. The aim of the current study was to evaluate plasma kynurenine as a predictive biomarker for CI-AKI and long-term complications, measured by the combined endpoint "major adverse kidney events" (MAKE) up to 120 days after CM application. Methods: In this prospective cohort study 245 patients undergoing coronary angiography were analyzed. Blood samples were obtained at baseline, 24h and 48h after contrast media (CM) application to diagnose CI-AKI. Patients were followed for 120 days for adverse clinical events including death, the need for dialysis, and a doubling of plasma creatinine. Occurrence of any of these events was summarized in the combined endpoint MAKE. Results: Preinterventional plasma kynurenine was not associated with CI-AKI. Patients who later developed MAKE displayed significantly increased preinterventional plasma kynurenine levels (p<0.0001). ROC analysis revealed that preinterventional kynurenine is highly predictive for MAKE (AUC=0.838; p<0.0001). The optimal cutoff was found at ≥3.5 µmol/L Using this cutoff, the Kaplan-Meier estimator demonstrated that concentrations of plasma kynurenine ≥3.5 µmol/L were significantly associated with a higher prevalence of MAKE until follow up (p<0.0001). This association remained significant in multivariate Cox regression models adjusted for relevant factors of long-term renal outcome. Conclusion: Preinterventional plasma kynurenine might serve as a highly predictive biomarker for MAKE up to 120 days after coronary angiography.

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“…Catabolites in the Kyn pathway of Trp catabolism are important for regulating the immune system and inflammation 10, 11. Emerging evidence also indicates that these catabolites play significant roles in cardiovascular pathophysiology 12, 13, 14…”

Section: Introductionmentioning

confidence: 99%

Indoleamine 2,3‐dioxygenase 1 in coronary atherosclerotic plaque enhances tissue factor expression in activated macrophages

Watanabe

Koyama

Yamashita

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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BackgroundRecent clinical studies have found that changes in the kynurenine (Kyn) pathway of tryptophan (Trp) metabolism are associated with cardiovascular events. However, the roles of the Kyn pathway on vascular wall thrombogenicity remain unknown. Indoleamine 2,3‐dioxygenase 1 (IDO1) is a rate‐limiting enzyme of the Kyn pathway.ObjectiveThe present study aimed to localize IDO1 in human coronary atherosclerotic plaques from patients with angina pectoris and define its role in plaque thrombogenicity.MethodsImmunohistochemical methods were applied to localize IDO1 in coronary atherosclerotic plaques from patients with stable (SAP) and unstable (UAP) angina pectoris. The role of IDO1 in tissue factor (TF) expression was investigated in THP‐1 macrophages activated by interferon (IFN)γ and tissue necrosis factor (TNF)α.ResultsWe localized IDO1 mainly in CD68‐positive macrophages within atherosclerotic plaques, and in close association with TF. Areas that were immunopositive for IDO1, TF, and CD3‐positive T lymphocytes were significantly larger in plaques from patients with UAP than SAP. Macrophages activated by IFNγ and TNFα upregulated IDO1 expression, increased the Kyn/Trp ratio and enhanced TF expression and activity, but not TF pathway inhibitor expression. The IDO1 inhibitor epacadostat significantly reduced the Kyn/Trp ratio, TF expression and activity, as well as NF‐κB (p65) binding activity in activated macrophages. Inhibition of the aryl hydrocarbon receptor that binds to Kyn, also reduced Kyn‐induced TF expression in activated macrophages.ConclusionIndoleamine 2,3‐dioxygenase 1 expressed in coronary atherosclerotic plaques might contribute to thrombus formation through TF upregulation in activated macrophages.

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Tryptophan-kynurenine pathway is dysregulated in inflammation and immune activation

Cited by 281 publications

References 213 publications

Tryptophan-Derived 3-Hydroxyanthranilic Acid Contributes to Angiotensin II–Induced Abdominal Aortic Aneurysm Formation in Mice In Vivo

Tryptophan-Derived 3-Hydroxyanthranilic Acid Contributes to Angiotensin II–Induced Abdominal Aortic Aneurysm Formation in Mice In Vivo

Pre-Interventional Kynurenine Predicts Medium-Term Outcome after Contrast Media Exposure Due to Coronary Angiography

Indoleamine 2,3‐dioxygenase 1 in coronary atherosclerotic plaque enhances tissue factor expression in activated macrophages

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