Inhibition of glutamine synthetase in monocytes from patients with acute-on-chronic liver failure resuscitates their antibacterial and inflammatory capacity

Korf, Hannelie; Plessis, Johannie Du; Pelt, Jos van; Groote, Sofie De; Cassiman, David; Verbeke, Len; Ghesquière, Bart; Fendt, Sarah-Maria; Bird, Matthew; Talebi, Ali; Haele, Matthias Van; Feio-Azevedo, Rita; Meelberghs, Lore; Roskams, Tania; Mookerjee, R.; Mehta, Gautam; Jalan, Rajiv; Gustot, Thierry; Laleman, Wim; Nevens, Frederik; Merwe, Schalk van der

doi:10.1136/gutjnl-2018-316888

Cited by 64 publications

(98 citation statements)

References 48 publications

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“…Moreover, the glutamine synthetase/glutaminase ratio of ACLF (EASL-CLIF ACLF) in patient-derived monocytes showed a positive association with disease severity scores including MELD. Remarkably, metabolic rewiring of the cells using a pharmacological inhibitor of glutamine synthetase, partially restored the inflammatory and phagocytic capacity of in vitro-generated as well as ACLF patients-derived monocytes and highlights its biological relevance (77).…”

Section: Monocytesmentioning

confidence: 89%

Abnormal Innate Immunity in Acute-on-Chronic Liver Failure: Immunotargets for Therapeutics

Khanam

Kottilil

2020

Front. Immunol.

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Acute-on-chronic liver failure (ACLF) is a severe life-threatening condition with high risk of multiorgan failure, sepsis, and mortality. ACLF activates a multifaceted interplay of both innate and adaptive immune response in the host which governs the overall outcome. Innate immune cells recognize the conserved elements of microbial and viral origin, both to extort instant defense by transforming into diverse modules of effector responses and to generate long-lasting immunity but can also trigger a massive intrahepatic immune inflammatory response. Acute insult results in the activation of innate immune cells which provokes cytokine and chemokine cascade and subsequently initiates aggressive systemic inflammatory response syndrome, hepatic damage, and high mortality in ACLF. Dysregulated innate immune response not only plays a critical role in disease progression but also potentially correlates with clinical disease severity indices including Child-Turcotte-Pugh, a model for end-stage liver disease, and sequential organ failure assessment score. A better understanding of the pathophysiological basis of the disease and precise immune mechanisms associated with liver injury offers a novel approach for the development of new and efficient therapies to treat this severely ill entity. Immunotherapies could be helpful in targeting immune-mediated organ damage which may constrain progression toward liver failure and eventually reduce the requirement for liver transplantation. Here, in this review we discuss the defects of different innate immune cells in ACLF which updates the current knowledge of innate immune response and provide potential targets for new therapeutic interventions.

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Section: Monocytesmentioning

confidence: 89%

Abnormal Innate Immunity in Acute-on-Chronic Liver Failure: Immunotargets for Therapeutics

Khanam

Kottilil

2020

Front. Immunol.

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“…Therefore, glutamine metabolism is considered to be another major feature of cancer cell metabolism besides Warburg effect. In recent years, more and more studies have confirmed that treatment targeting glutamine metabolism can effectively inhibit the progress of many cancers (Meijer et al, 2018;Korf et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

miR‐145 inhibits glutamine metabolism through c‐myc/GLS1 pathways in ovarian cancer cells

et al. 2019

Cell Biology International

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miR‐145 has been found to be a participant in cancer metastasis and glucose metabolism in ovarian cancer. However, the role of glutamine metabolism in ovarian cancer remains unclear. In this study, we aim to elucidate the molecular mechanism underlying the regulation of glutamine metabolism by miR‐145 in ovarian cancer cells. The messenger RNA (mRNA) levels of miR‐145 and glutaminase 1 (GLS1) were examined by quantitative real‐time polymerase chain reaction (qRT‐PCR). The protein levels of c‐myc and GLS1 were detected by western blot analysis. Luciferase reporter assays were used to validate c‐myc was a target of miR‐145. Glutamine metabolism was analyzed using assay kits. In addition, we performed luciferase reporter assays and chromatin immunoprecipitation assay to validate c‐myc transcription activated GLS1 and promoted GLS1 expression. The qRT‐PCR demonstrated that the mRNA level of miR‐145 and GLS1 was negatively correlated in ovarian cancer tissues and cell lines. Kaplan–Meier survival analysis and the log‐rank test showed that patients with high miR‐145 expression had significantly increased the overall survival. The overexpression of miR‐145 inhibited glutamine consumption, α‐ketoglutarate production, and cellular ATP levels. Furthermore, we found miR‐145 inhibited glutamine metabolism by targeting c‐myc. Moreover, c‐myc could promote GLS1 expression by transcription activated. Together, our results revealed that miR‐145 inhibited glutamine metabolism through c‐myc/GLS1 pathways in ovarian cancer cells, which may improve the current strategy of ovarian cancer diagnosis and therapy.

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“…Indeed, T cell proliferation, tumour necrosis factor-alpha (TNF-α) and IL-6 production in response to TLR stimulation and uptake of Escherichia coli were reduced 38. A third study showed that monocytes from patients with ACLF had elevated frequencies of IL-10-producing cells, reduced HLA-DR expression and impaired phagocytic and oxidative burst capacity 39. Transcriptomic data revealed a profile of alternatively polarised, tolerant monocytes.…”

Section: Pathophysiology Of Ad and Aclfmentioning

confidence: 99%

“…Transcriptomic data revealed a profile of alternatively polarised, tolerant monocytes. Interestingly, the pharmacological inhibition of glutamine synthesis favouring glutaminolysis improved the monocytes phagocytic and inflammatory 39. Similarly, neutrophils from patients with ACLF present severe defects of phagocytosis and ability to kill ingested bacteria despite marked activation.…”

Section: Pathophysiology Of Ad and Aclfmentioning

confidence: 99%

Albumin in decompensated cirrhosis: new concepts and perspectives

Bernardi

Angeli

Clariá

et al. 2020

Gut

Self Cite

213

221

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The pathophysiological background of decompensated cirrhosis is characterised by a systemic proinflammatory and pro-oxidant milieu that plays a major role in the development of multiorgan dysfunction. Such abnormality is mainly due to the systemic spread of bacteria and/or bacterial products from the gut and danger-associated molecular patterns from the diseased liver triggering the release of proinflammatory mediators by activating immune cells. The exacerbation of these processes underlies the development of acute-on-chronic liver failure. A further mechanism promoting multiorgan dysfunction and failure likely consists with a mitochondrial oxidative phosphorylation dysfunction responsible for systemic cellular energy crisis. The systemic proinflammatory and pro-oxidant state of patients with decompensated cirrhosis is also responsible for structural and functional changes in the albumin molecule, which spoil its pleiotropic non-oncotic properties such as antioxidant, scavenging, immune-modulating and endothelium protective functions. The knowledge of these abnormalities provides novel targets for mechanistic treatments. In this respect, the oncotic and non-oncotic properties of albumin make it a potential multitarget agent. This would expand the well-established indications to the use of albumin in decompensated cirrhosis, which mainly aim at improving effective volaemia or preventing its deterioration. Evidence has been recently provided that long-term albumin administration to patients with cirrhosis and ascites improves survival, prevents complications, eases the management of ascites and reduces hospitalisations. However, variant results indicate that further investigations are needed, aiming at confirming the beneficial effects of albumin, clarifying its optimal dosage and administration schedule and identify patients who would benefit most from long-term albumin administration.

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Inhibition of glutamine synthetase in monocytes from patients with acute-on-chronic liver failure resuscitates their antibacterial and inflammatory capacity

Cited by 64 publications

References 48 publications

Abnormal Innate Immunity in Acute-on-Chronic Liver Failure: Immunotargets for Therapeutics

Abnormal Innate Immunity in Acute-on-Chronic Liver Failure: Immunotargets for Therapeutics

miR‐145 inhibits glutamine metabolism through c‐myc/GLS1 pathways in ovarian cancer cells

Albumin in decompensated cirrhosis: new concepts and perspectives

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