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Kynurenine Pathway: A Bridge between Health and Disease
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Kynurenine Pathway: A Bridge between Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 12734

Special Issue Editors

Dr. Astrid Parenti

E-Mail Website
Guest Editor
Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy
Interests: nitric oxide; endothelium; melanoma biology; angiogenesis; vascular inflammation; cardiovascular disease
Special Issues, Collections and Topics in MDPI journals
Dr. Eid Ali Hussein

E-Mail Website
Guest Editor
1. Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, 2713 Doha, Qatar
2. Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, 2713 Doha, Qatar
Interests: molecular pharmacology; Epac signaling; vascular alpha 2 adrenergic receptors

Special Issue Information

Dear Colleagues,

The kynurenine pathway (KP) is the major route for tryptophan catabolism. The first and limiting step in KP is primarily controlled by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), which produce a range of biologically active metabolites, including kynurenine itself, kynurenic acid and nicotinamide adenine dinucleotide (NAD+). The products of KP are involved, directly or indirectly, in a wide range of mechanisms of the endocrine, haemopoietic, immune, cardiovascular (CV) and nervous system. Tryptophan is indeed essential for protein synthesis, and it is also converted into key neurotransmitters’ serotonin and tryptamine. Increased KP has been associated with several CV diseases, and, recently, significant interest has been focused on KP-induced immune escape, as demonstrated by pharmacological inhibition of IDO1 and TDO for cancer therapy.

In this Special Issue, we seek papers that present the latest evidence on KP research and discuss interplay between KP deregulation and human health and disease.

Dr. Astrid Parenti
Dr. Eid Ali Hussein
Guest Editors

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Keywords

  • cancer
  • cardiovascular disease
  • immune escape
  • inflammation
  • brain disorders
  • neurodegeneration
  • aging
  • oxidative stress
  • indoleamine 2,3-dioxygenase
  • tryptophan 2,3-dioxygenase

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Published Papers (3 papers)

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Research

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13 pages, 3259 KiB  
Article
Tolerogenic IDO1+CD83− Langerhans Cells in Sentinel Lymph Nodes of Patients with Melanoma
by Gianni Gerlini, Paola Di Gennaro, Nicola Pimpinelli, Serena Sestini and Lorenzo Borgognoni
Int. J. Mol. Sci. 2022, 23(7), 3441; https://doi.org/10.3390/ijms23073441 - 22 Mar 2022
Cited by 6 | Viewed by 2134
Abstract
Langerhans cells (LCs) are crucial regulators of anti-cancer immune responses. Cancer, however, can alter DCs functions leading to tolerance. The enzyme indoleamine 2,3-dioxygenase (IDO1) plays a crucial role in this process. In sentinel lymph nodes (SLNs) of patients with melanoma, LCs show phenotypical [...] Read more.
Langerhans cells (LCs) are crucial regulators of anti-cancer immune responses. Cancer, however, can alter DCs functions leading to tolerance. The enzyme indoleamine 2,3-dioxygenase (IDO1) plays a crucial role in this process. In sentinel lymph nodes (SLNs) of patients with melanoma, LCs show phenotypical and functional alterations favoring tolerance. Herein we aimed to investigate IDO1 expression in SLN LCs from patients with melanoma. We showed by immunofluorescence analysis that a portion of Langerin+ LCs, located in the SLN T cell-rich area, displayed the typical dendritic morphology and expressed IDO1. There was no significant difference in the expression of IDO between SLN with or without metastases. Double IDO1/CD83 staining identified four LCs subsets: real mature IDO1−CD83+ LCs; real immature IDO1−CD83− LCs; tolerogenic mature IDO1+CD83+ LCs; tolerogenic immature IDO1+CD83− LCs. The latter subset was significantly increased in metastatic SLNs as compared to negative ones (p < 0.05), and in SLN LCs of patients with mitotic rate (MR) > 1 in primary melanoma, as compared to MR ≤ 1 (p < 0.05). Finally, immature SLN LCs, after in vitro stimulation by inflammatory cytokines, acquired a maturation profile by CD83 up-regulation. These results provide new input for immunotherapeutic approaches targeting in vivo LC of patients with melanoma. Full article
(This article belongs to the Special Issue Kynurenine Pathway: A Bridge between Health and Disease)
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16 pages, 2345 KiB  
Article
Alterations in Kynurenine and NAD+ Salvage Pathways during the Successful Treatment of Inflammatory Bowel Disease Suggest HCAR3 and NNMT as Potential Drug Targets
by Artur Wnorowski, Sylwia Wnorowska, Jacek Kurzepa and Jolanta Parada-Turska
Int. J. Mol. Sci. 2021, 22(24), 13497; https://doi.org/10.3390/ijms222413497 - 16 Dec 2021
Cited by 27 | Viewed by 4502
Abstract
A meta-analysis of publicly available transcriptomic datasets was performed to identify metabolic pathways profoundly implicated in the progression and treatment of inflammatory bowel disease (IBD). The analysis revealed that genes involved in tryptophan (Trp) metabolism are upregulated in Crohn’s disease (CD) and ulcerative [...] Read more.
A meta-analysis of publicly available transcriptomic datasets was performed to identify metabolic pathways profoundly implicated in the progression and treatment of inflammatory bowel disease (IBD). The analysis revealed that genes involved in tryptophan (Trp) metabolism are upregulated in Crohn’s disease (CD) and ulcerative colitis (UC) and return to baseline after successful treatment with infliximab. Microarray and mRNAseq profiles from multiple experiments confirmed that enzymes responsible for Trp degradation via the kynurenine pathway (IDO1, KYNU, IL4I1, KMO, and TDO2), receptor of Trp metabolites (HCAR3), and enzymes catalyzing NAD+ turnover (NAMPT, NNMT, PARP9, CD38) were synchronously coregulated in IBD, but not in intestinal malignancies. The modeling of Trp metabolite fluxes in IBD indicated that changes in gene expression shifted intestinal Trp metabolism from the synthesis of 5-hydroxytryptamine (5HT, serotonin) towards the kynurenine pathway. Based on pathway modeling, this manifested in a decline in mucosal Trp and elevated kynurenine (Kyn) levels, and fueled the production of downstream metabolites, including quinolinate, a substrate for de novo NAD+ synthesis. Interestingly, IBD-dependent alterations in Trp metabolites were normalized in infliximab responders, but not in non-responders. Transcriptomic reconstruction of the NAD+ pathway revealed an increased salvage biosynthesis and utilization of NAD+ in IBD, which normalized in patients successfully treated with infliximab. Treatment-related changes in NAD+ levels correlated with shifts in nicotinamide N-methyltransferase (NNMT) expression. This enzyme helps to maintain a high level of NAD+-dependent proinflammatory signaling by removing excess inhibitory nicotinamide (Nam) from the system. Our analysis highlights the prevalent deregulation of kynurenine and NAD+ biosynthetic pathways in IBD and gives new impetus for conducting an in-depth examination of uncovered phenomena in clinical studies. Full article
(This article belongs to the Special Issue Kynurenine Pathway: A Bridge between Health and Disease)
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Review

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37 pages, 2388 KiB  
Review
The Kynurenine Pathway—New Linkage between Innate and Adaptive Immunity in Autoimmune Endocrinopathies
by Anna Krupa and Irina Kowalska
Int. J. Mol. Sci. 2021, 22(18), 9879; https://doi.org/10.3390/ijms22189879 - 13 Sep 2021
Cited by 43 | Viewed by 5411
Abstract
The kynurenine pathway (KP) is highly regulated in the immune system, where it promotes immunosuppression in response to infection or inflammation. Indoleamine 2,3-dioxygenase 1 (IDO1), the main enzyme of KP, has a broad spectrum of activity on immune cells regulation, controlling the balance [...] Read more.
The kynurenine pathway (KP) is highly regulated in the immune system, where it promotes immunosuppression in response to infection or inflammation. Indoleamine 2,3-dioxygenase 1 (IDO1), the main enzyme of KP, has a broad spectrum of activity on immune cells regulation, controlling the balance between stimulation and suppression of the immune system at sites of local inflammation, relevant to a wide range of autoimmune and inflammatory diseases. Various autoimmune diseases, among them endocrinopathies, have been identified to date, but despite significant progress in their diagnosis and treatment, they are still associated with significant complications, morbidity, and mortality. The precise cellular and molecular mechanisms leading to the onset and development of autoimmune disease remain poorly clarified so far. In breaking of tolerance, the cells of the innate immunity provide a decisive microenvironment that regulates immune cells’ differentiation, leading to activation of adaptive immunity. The current review provided a comprehensive presentation of the known role of IDO1 and KP activation in the regulation of the innate and adaptive arms of the immune system. Significant attention has been paid to the immunoregulatory role of IDO1 in the most prevalent, organ-specific autoimmune endocrinopathies—type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis. Full article
(This article belongs to the Special Issue Kynurenine Pathway: A Bridge between Health and Disease)
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