Inhibition of the kynurenine pathway protects against reactive microglial-associated reductions in the complexity of primary cortical neurons

O’Farrell, Katherine; Fagan, E.M.; Connor, Thomas J.; Harkin, Andrew

doi:10.1016/j.ejphar.2017.07.008

Cited by 30 publications

(20 citation statements)

References 64 publications

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“…Kynureninase is a catalytic enzyme encoded by KYNU gene, acting within the kynurenine pathway of tryptophan metabolism that is related to immunomodulation and inflammation 52 . In murine macrophages and microglial cells, kynureninase activity and expression was activated by IFN-γ 53 , 54 . In patients with inflammatory skin diseases, the levels of mRNA and protein expression for KYNU were found up-regulated in skin lesions compared to non-involved skins, and positively correlated to disease severity 55 , 56 .…”

Section: Discussionmentioning

confidence: 99%

Systematic Analysis of Differential Expression Profile in Rheumatoid Arthritis Chondrocytes Using Next-Generation Sequencing and Bioinformatics Approaches

Chen¹,

Chang²,

Wu³

et al. 2018

Int. J. Med. Sci.

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Cartilage destruction in rheumatoid arthritis (RA) occurs primarily in the pannus-cartilage interface. The close contact of the synovium-cartilage interface implicates crosstalk between synovial fibroblasts and chondrocytes. The aim of this study is to explore the differentially expressed genes and novel microRNA regulations potentially implicated in the dysregulated cartilage homeostasis in joint destruction of RA. Total RNAs were extracted from human primary cultured normal and RA chondrocytes for RNA and small RNA expression profiling using next-generation sequencing. Using systematic bioinformatics analyses, we identified 463 differentially expressed genes in RA chondrocytes were enriched in biological functions related to altered cell cycle process, inflammatory response and hypoxic stimulation. Moreover, fibroblast growth factor 9 (FGF9), kynureninase (KYNU), and regulator of cell cycle (RGCC) were among the top dysregulated genes identified to be potentially affected in the RA joint microenvironment, having similar expression patterns observed in arrays of clinical RA synovial tissues from the Gene Expression Omnibus database. Additionally, among the 31 differentially expressed microRNAs and 10 candidate genes with potential microRNA-mRNA interactions in RA chondrocytes, the novel miR-140-3p-FGF9 interaction was validated in different microRNA prediction databases, and proposed to participate in the pathogenesis of joint destruction through dysregulated cell growth in RA. The findings provide new perspectives for target genes in the management of cartilage destruction in RA.

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Section: Discussionmentioning

confidence: 99%

Systematic Analysis of Differential Expression Profile in Rheumatoid Arthritis Chondrocytes Using Next-Generation Sequencing and Bioinformatics Approaches

Chen¹,

Chang²,

Wu³

et al. 2018

Int. J. Med. Sci.

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“…In healthy subjects, a well-adjusted system is established in the KP via the action of kynurenines aminotransferases (KATs) on kynurenic acid or quinolinic acid by (KMO) [141]. Kynurenic acid has been reported to promote neuroprotective and immunosuppressive actions in the CNS and plays a role as an NMDA antagonist, blocking this glutamatergic receptor.…”

Section: Kp and Neurological Manifestationsmentioning

confidence: 99%

Neurological and Inflammatory Manifestations in Sjögren’s Syndrome: The Role of the Kynurenine Metabolic Pathway

Oliveira

Fantucci

Adriano

et al. 2018

IJMS

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For decades, neurological, psychological, and cognitive alterations, as well as other glandular manifestations (EGM), have been described and are being considered to be part of Sjögren’s syndrome (SS). Dry eye and dry mouth are major findings in SS. The lacrimal glands (LG), ocular surface (OS), and salivary glands (SG) are linked to the central nervous system (CNS) at the brainstem and hippocampus. Once compromised, these CNS sites may be responsible for autonomic and functional disturbances that are related to major and EGM in SS. Recent studies have confirmed that the kynurenine metabolic pathway (KP) can be stimulated by interferon-γ (IFN-γ) and other cytokines, activating indoleamine 2,3-dioxygenase (IDO) in SS. This pathway interferes with serotonergic and glutamatergic neurotransmission, mostly in the hippocampus and other structures of the CNS. Therefore, it is plausible that KP induces neurological manifestations and contributes to the discrepancy between symptoms and signs, including manifestations of hyperalgesia and depression in SS patients with weaker signs of sicca, for example. Observations from clinical studies in acquired immune deficiency syndrome (AIDS), graft-versus-host disease, and lupus, as well as from experimental studies, support this hypothesis. However, the obtained results for SS are controversial, as discussed in this study. Therapeutic strategies have been reexamined and new options designed and tested to regulate the KP. In the future, the confirmation and application of this concept may help to elucidate the mosaic of SS manifestations.

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“…QA is an N ‐methyl‐ d ‐aspartate receptor (NMDAR) agonist, and can cause excessive glutamate excitotoxicity to neurons . QA is synthesized by microglia , and neurons cultured in supernatant from IFNγ‐stimulated microglia exhibit reduced neurite outgrowth and complexity, which can be prevented by pretreatment of microglia with an IDO inhibitor or an NMDAR inhibitor . Notably, KA is an NMDAR antagonist , which can protect neurons from excitotoxic damage.…”

Section: Introductionmentioning

confidence: 99%

Cognitive Dysfunction in Systemic Lupus Erythematosus: A Case for Initiating Trials

Kello

Anderson

Diamond

2019

Arthritis & Rheumatology

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Cognitive dysfunction (CD) is an insidious and underdiagnosed manifestation of systemic lupus erythematosus (SLE) that has a considerable impact on quality of life, which can be devastating. Given the inconsistencies in the modes of assessment and the difficulties in attribution to SLE, the reported prevalence of CD ranges from 5% to 80%. Although clinical studies of SLE‐related CD have been hampered by heterogeneous subject populations and a lack of sensitive and standardized cognitive tests or other validated objective biomarkers for CD, there are, nonetheless, strong data from mouse models and from the clinical arena that show CD is related to known disease mechanisms. Several cytokines, inflammatory molecules, and antibodies have been associated with CD. Proposed mechanisms for antibody‐ and cytokine‐mediated neuronal injury include the abrogation of blood–brain barrier integrity with direct access of soluble molecules in the circulation to the brain and ensuing neurotoxicity and microglial activation. No treatments for SLE‐mediated CD exist, but potential candidates include agents that inhibit microglial activation, such as angiotensin‐converting enzyme inhibitors, or that protect blood–brain barrier integrity, such as C5a receptor blockers. Structural and functional neuroimaging data have shown a range of regional abnormalities in metabolism and white matter microstructural integrity in SLE patients that correlate with CD and could in the future become diagnostic tools and outcome measures in clinical trials aimed at preserving cognitive function in SLE.

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Inhibition of the kynurenine pathway protects against reactive microglial-associated reductions in the complexity of primary cortical neurons

Cited by 30 publications

References 64 publications

Systematic Analysis of Differential Expression Profile in Rheumatoid Arthritis Chondrocytes Using Next-Generation Sequencing and Bioinformatics Approaches

Systematic Analysis of Differential Expression Profile in Rheumatoid Arthritis Chondrocytes Using Next-Generation Sequencing and Bioinformatics Approaches

Neurological and Inflammatory Manifestations in Sjögren’s Syndrome: The Role of the Kynurenine Metabolic Pathway

Cognitive Dysfunction in Systemic Lupus Erythematosus: A Case for Initiating Trials

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