Kynurenine monooxygenase regulates inflammation during critical illness and recovery in experimental acute pancreatitis

Hayes, Alastair; Zheng, Xiaozhong; O’Kelly, James; Neyton, Lucile; Bochkina, Natalia; Uings, Iain; Liddle, John; Baillie, J Kenneth; Just, George; Binnie, Margaret; Homer, Natalie; Murray, T.; Baily, James; McGuire, Kris; Skouras, Christos; Garden, O. James; Webster, Scott P.; Iredale, John P.; Howie, Sarah; Mole, Damian J.

doi:10.1016/j.celrep.2023.112763

Cited by 11 publications

(3 citation statements)

References 66 publications

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“…Previous studies have suggested that KMO exerts a critical regulatory role in macrophages, with emerging evidence highlighting its close interplay with macrophage inflammatory responses and immune modulation [ 34 ]. Heightened KMO activity augments flux within the kynurenine pathway, resulting in excessive generation of pro-inflammatory mediators, obvious quinolinic acid [ 47 ]. Consequently, this elicits robust inflammatory cascades.…”

Section: Discussionmentioning

confidence: 99%

Identification and experimental validation of KMO as a critical immune-associated mitochondrial gene in unstable atherosclerotic plaque

Liao,

Shen,

Bao

et al. 2024

J Transl Med

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Background The heightened risk of cardiovascular and cerebrovascular events is associated with the increased instability of atherosclerotic plaques. However, the lack of effective diagnostic biomarkers has impeded the assessment of plaque instability currently. This study was aimed to investigate and identify hub genes associated with unstable plaques through the integration of various bioinformatics tools, providing novel insights into the detection and treatment of this condition. Methods Weighted Gene Co-expression Network Analysis (WGCNA) combined with two machine learning methods were used to identify hub genes strongly associated with plaque instability. The cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) method was utilized to assess immune cell infiltration patterns in atherosclerosis patients. Additionally, Gene Set Variation Analysis (GSVA) was conducted to investigate the potential biological functions, pathways, and mechanisms of hub genes associated with unstable plaques. To further validate the diagnostic efficiency and expression of the hub genes, immunohistochemistry (IHC), quantitative real-time polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA) were performed on collected human carotid plaque and blood samples. Immunofluorescence co-staining was also utilized to confirm the association between hub genes and immune cells, as well as their colocalization with mitochondria. Results The CIBERSORT analysis demonstrated a significant decrease in the infiltration of CD8 T cells and an obvious increase in the infiltration of M0 macrophages in patients with atherosclerosis. Subsequently, two highly relevant modules (blue and green) strongly associated with atherosclerotic plaque instability were identified. Through intersection with mitochondria-related genes, 50 crucial genes were identified. Further analysis employing least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine recursive feature elimination (SVM-RFE) algorithms revealed six hub genes significantly associated with plaque instability. Among them, NT5DC3, ACADL, SLC25A4, ALDH1B1, and MAOB exhibited positive correlations with CD8 T cells and negative correlations with M0 macrophages, while kynurenine 3-monooxygenas (KMO) demonstrated a positive correlation with M0 macrophages and a negative correlation with CD8 T cells. IHC and RT-qPCR analyses of human carotid plaque samples, as well as ELISA analyses of blood samples, revealed significant upregulation of KMO and MAOB expression, along with decreased ALDH1B1 expression, in both stable and unstable samples compared to the control samples. However, among the three key genes mentioned above, only KMO showed a significant increase in expression in unstable plaque samples compared to stable plaque samples. Furthermore, the expression patterns of KMO in human carotid unstable plaque tissues and cultured mouse macrophage cell lines were assessed using immunofluorescence co-staining techniques. Finally, lentivirus-mediated KMO silencing was successfully transduced into the aortas of high-fat-fed ApoE-/- mice, with results indicating that KMO silencing attenuated plaque formation and promoted plaque stability in ApoE-/- mice. Conclusions The results suggest that KMO, a mitochondria-targeted gene associated with macrophage cells, holds promise as a valuable diagnostic biomarker for assessing the instability of atherosclerotic plaques.

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Section: Discussionmentioning

confidence: 99%

Identification and experimental validation of KMO as a critical immune-associated mitochondrial gene in unstable atherosclerotic plaque

Liao,

Shen,

Bao

et al. 2024

J Transl Med

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“…Extracts were dried down under nitrogen and reconstituted in LC-MS grade water (100 μL). 10 μL was injected onto a column (Ace C18-PFP column; 100 x 2.1 mm internal diameter 1.7 μm; HiChrom (VWR, Lutterworth)) using an Acquity I-Class UPLC liquid chromatography system (Waters) linked to a QTRAP 6500+ mass spectrometer (AB Sciex) 17 . The flow rate was set at 0.4 mL/min with a column temperature of 40°C.…”

Section: Methodsmentioning

confidence: 99%

Kynurenine monooxygenase blockade reduces endometriosis-like lesions, improves visceral hyperalgesia, and rescues mice from a negative behavioural phenotype in experimental endometriosis

Higgins,

Simitsidellis,

Zheng

et al. 2024

Preprint

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Endometriosis is a common and debilitating neuro-inflammatory disorder that is associated with chronic pain. Definitive diagnosis is based on the presence of endometrial-like tissue (lesions) in sites outside the uterus. Kynurenine monooxygenase (KMO) is a mitochondrial enzyme of tryptophan metabolism that regulates inflammation and immunity. Here, we show that KMO is expressed in epithelial cells in human endometriosis tissue lesions and in corresponding lesions in a mouse model of endometriosis. In mice, oral treatment with the potent KMO inhibitor KNS898 induced a biochemical state of KMO blockade with accumulation of kynurenine, diversion to kynurenic acid and ablation of 3-hydroxykynurenine production. In the mouse model of endometriosis, KMO inhibition improved histological outcomes and endometriosis pain-like behaviours, even when KNS898 treatment commenced one week after initiation of lesions. Taken together, these results suggest that KMO blockade is a promising new non-hormonal therapeutic modality for endometriosis.

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“…Both IFN-γ and IL-1β induce the expression of the Kmo gene as well as its upstream enzymes (i.e., IDO-1, TDO) resulting in increased availability of KYN as KMO substrate and subsequently elevated levels of 3-HK. Both pharmacological inhibition of KMO and knockout of the Kmo gene cause increased levels of KYN and its conversion to KYNA [44][45][46], the latter being performed by kynurenine aminotransferases (KATs) through the KYNA branch (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

The roles of the kynurenine pathway in COVID-19 neuropathogenesis

Dehhaghi,

Heydari,

Panahi

et al. 2024

Infection

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the highly contagious respiratory disease Corona Virus Disease 2019 (COVID-19) that may lead to various neurological and psychological disorders that can be acute, lasting days to weeks or months and possibly longer. The latter is known as long-COVID or more recently post-acute sequelae of COVID (PASC). During acute COVID-19 infection, a strong inflammatory response, known as the cytokine storm, occurs in some patients. The levels of interferon‐γ (IFN‐γ), interferon-β (IFN-β), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) are particularly increased. These cytokines are known to activate the enzyme indoleamine 2,3-dioxygenase 1 (IDO-1), catalysing the first step of tryptophan (Trp) catabolism through the kynurenine pathway (KP) leading to the production of several neurotoxic and immunosuppressive metabolites. There is already data showing elevation in KP metabolites both acutely and in PASC, especially regarding cognitive impairment. Thus, it is likely that KP involvement is significant in SARS-CoV-2 pathogenesis especially neurologically.

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Kynurenine monooxygenase regulates inflammation during critical illness and recovery in experimental acute pancreatitis

Cited by 11 publications

References 66 publications

Identification and experimental validation of KMO as a critical immune-associated mitochondrial gene in unstable atherosclerotic plaque

Identification and experimental validation of KMO as a critical immune-associated mitochondrial gene in unstable atherosclerotic plaque

Kynurenine monooxygenase blockade reduces endometriosis-like lesions, improves visceral hyperalgesia, and rescues mice from a negative behavioural phenotype in experimental endometriosis

The roles of the kynurenine pathway in COVID-19 neuropathogenesis

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