NADPH oxidase depletion in neutrophils from patients with cirrhosis and restoration via toll-like receptor 7/8 activation

Rolas, Loïc; Boussif, Abdelali; Weiss, Emmanuel; Lettéron, Philippe; Haddad, Oualid; El-Benna, Jamel; Rautou, Pierre‐Emmanuel; Moreau, Richard; Périanin, Axel

doi:10.1136/gutjnl-2016-313443

Cited by 32 publications

(52 citation statements)

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“…(40,41) Moreover, neutrophil function has been reported to be impaired in acute-on-chronic liver failure, thus suggesting that both recruitment and function of neutrophils may be altered in the context of AH. (42)(43)(44) Whether the recruitment of neutrophils to the DR plays a deleterious role in the progression of the diseases or helps to orchestrate inflammatory response as a result of an acute-on-chronic injury is unknown.…”

Section: Discussionmentioning

confidence: 99%

Ductular reaction cells display an inflammatory profile and recruit neutrophils in alcoholic hepatitis

Aguilar-Bravo¹,

Rodrigo-Torres²,

Coll³

et al. 2018

Journal of Hepatology

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Section: Discussionmentioning

confidence: 99%

Ductular reaction cells display an inflammatory profile and recruit neutrophils in alcoholic hepatitis

Aguilar-Bravo¹,

Rodrigo-Torres²,

Coll³

et al. 2018

Journal of Hepatology

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“…Innate immune dysfunctions in CAID have been well described. In patients presenting alcohol-related liver diseases (ALD), profound impaired oxidative burst and bactericidal functions of polymorphonuclear neutrophils (PMNs) and monocytes were observed [6][7][8][9][10] . In patients with acute liver failure (ALF) and ACLF, pro-inflammatory conditions could drive an in vivo anti-inflammatory monocyte phenotype which was associated with a defective anti-bacterial response in vitro [11][12][13] .…”

Section: Introductionmentioning

confidence: 99%

CD8+ T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis-associated immune dysfunction

et al. 2019

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a b s t r a c tBackground: Cirrhosis-associated immune dysfunction (CAID) contributes to high sepsis risk in patients with chronic liver disease. Various innate and; to a lesser extent; adaptive immune dysfunctions have been described as contributors to CAID leading to immune-paresis and impaired anti-microbial response in cirrhosis. In this study, we examined the phenotype of CD8 + T cells in chronic liver disease with the aim to evaluate changes that might contribute to impaired immune responses. Methods: Sixty patients with cirrhosis were prospectively recruited for this study. CD8 + T cells from peripheral blood, ascites and liver explants were characterized using flow cytometry and immunohistochemistry, respectively. The transcriptional signature of flow-sorted HLA-DR + CD8 + T cells was performed using Nanostring TM technology. HLA-DR + CD8 + T cells interactions with PBMCs and myeloid cells were tested in vitro . Findings: Peripheral CD8 + T cells from cirrhotic patients displayed an altered phenotype characterized by high HLA-DR and TIM-3 surface expression associated with concomitant infections and disease severity, respectively. Paired peritoneal CD8 + T cells expressed more pronounced levels of HLA-DR and PD-1 compared to peripheral CD8 + T cells. HLA-DR + CD8 + T cells were enriched in cirrhotic livers compared to controls. TIM-3, CTLA-4 and PD-1 levels were highly expressed on HLA-DR + CD8 + T cells and co-expression of HLA-DR and PD1 was higher in patients with poor disease outcomes. Genes involved in cytokines production and intracellular signalling pathways were strongly down-regulated in HLA-DR + CD8 + T cells. In comparison to their HLA-DR − counterparts, HLA-DR + CD8 + T cells promoted less proliferation of PBMCs and induced phenotypic and functional dysfunctions in monocytes and neutrophils in vitro . Interpretation: In patients with cirrhosis, CD8 + T cells display a phenotypic, functional and transcriptional profile which may contribute to CAID.

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“…Neutrophils from patients with decompensated alcoholic cirrhosis exhibit a marked under-expression of gp91 phox , p22 phox , p47 phox and mTOR. Gp91 phox turned out to be depleted by degradation mediated by elastase in patients' plasma, and by a deficient mTOR-dependent translational machinery (5). Interestingly, the deficient ROS production was reversed through activation of intracellular TLR7/8 involving de novo gp91 phox synthesis via a mTOR-dependent process (5).…”

Section: Jm Blandermentioning

confidence: 99%

“…Gp91 phox turned out to be depleted by degradation mediated by elastase in patients' plasma, and by a deficient mTOR-dependent translational machinery (5). Interestingly, the deficient ROS production was reversed through activation of intracellular TLR7/8 involving de novo gp91 phox synthesis via a mTOR-dependent process (5). Neutrophils contribute to microbial elimination via myeloperoxidase exocytosis.…”

Section: Jm Blandermentioning

confidence: 99%

Invited Speakers

2018

Eur J Clin Investigation

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Since changes in intracellular [Ca 2+ ] ([Ca 2+ ] i ) homeostasis, mitochondrial dysfunction and reactive oxygen species (ROS) are tightly connected. For instance, an increase in [Ca 2+ ] i affects mitochondrial [Ca 2+ ] and in most cases it is associated with an increased mitochondrial ROS formation, leading to the opening of the permeability transition pore (PTP), mitochondrial dysfunction and cell death. On the other hand, ROS modify [Ca 2+ ] I homeostasis by acting at various sites involved in intracellular Ca 2+ fluxes. The changes induced by [Ca 2+ ] I on ROS generation and vice versa are very rapid, making it difficult to elucidate the primary event under both physiological and pathological conditions. An additional matter of complexity is related to available techniques. While various methods are available to induce a primary and direct rise in [Ca 2+ ] I , the existing protocols to trigger ROS production are far from being specific. An increase in ROS is generally obtained as a consequence of the exogenous administration of an oxidant (mostly H 2 O 2 ) or by applying pathological stimuli (i.e., respiratory chain inhibition) that inevitably trigger several other effects, including alterations in [Ca 2+ ] i homeostasis. Here we investigated the effects of a primary increase in mitochondrial ROS levels induced by MitoParaquat (MitoPQ) a paraquat derivative targeted to mitochondria, which causes a dose-dependent selective increase in superoxide levels. In neonatal rat ventricular cardiomyocytes (NRVMs) high doses of MitoPQ (>100 nM) altered [Ca 2+ ] i homeostasis, hampered mitochondrial function due to permeability transition pore opening, eventually leading to cell death. On the other hand, low doses of MitoPQ caused a decreased susceptibility of neonatal rat ventricular myocytes (NRVMs) to anoxia/reoxygenation injury and profound protection in an in vivo mouse model of ischaemia/ reperfusion. Protection was obeserved also when a slight increase in mitochondrial ROS formation resulted from overexpressing the mitochondrial Ca 2+ uniporter (MCU). Demographic development in many countries reveals that the number of elderly has increased and will increase more and more within the next decades. However, while average life expectancy has increased markedly throughout the last century, this has not been accompanied by an equivalent increase in healthy life expectancy. Indeed, chronic, low-grade inflammation also frequently referred to as inflammaging has been acknowledged as a major characteristic of aging also being suggested to be critically involved in aging-associated decline of many organs including adipose tissue and skeletal muscle but also the liver and the gut. Despite intense research efforts molecular mechanisms underlying inflammaging have not yet been fully understood. Results of several epidemiological studies also suggest that age and herein especially older age increases the odds to develop diseases among them many metabolic diseases like non-alcoholic fatty liver dis...

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NADPH oxidase depletion in neutrophils from patients with cirrhosis and restoration via toll-like receptor 7/8 activation

Cited by 32 publications

References 50 publications

Ductular reaction cells display an inflammatory profile and recruit neutrophils in alcoholic hepatitis

Ductular reaction cells display an inflammatory profile and recruit neutrophils in alcoholic hepatitis

CD8+ T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis-associated immune dysfunction

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