Publications
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Singanayagam A, Triantafyllou E, 2021, Macrophages in Chronic Liver Failure: Diversity, Plasticity and Therapeutic Targeting, Frontiers in Immunology, Vol: 12
<jats:p>Chronic liver injury results in immune-driven progressive fibrosis, with risk of cirrhosis development and impact on morbidity and mortality. Persistent liver cell damage and death causes immune cell activation and inflammation. Patients with advanced cirrhosis additionally experience pathological bacterial translocation, exposure to microbial products and chronic engagement of the immune system. Bacterial infections have a high incidence in cirrhosis, with spontaneous bacterial peritonitis being the most common, while the subsequent systemic inflammation, organ failure and immune dysregulation increase the mortality risk. Tissue-resident and recruited macrophages play a central part in the development of inflammation and fibrosis progression. In the liver, adipose tissue, peritoneum and intestines, diverse macrophage populations exhibit great phenotypic and functional plasticity determined by their ontogeny, epigenetic programming and local microenvironment. These changes can, at different times, promote or ameliorate disease states and therefore represent potential targets for macrophage-directed therapies. In this review, we discuss the evidence for macrophage phenotypic and functional alterations in tissue compartments during the development and progression of chronic liver failure in different aetiologies and highlight the potential of macrophage modulation as a therapeutic strategy for liver disease.</jats:p>
Triantafyllou E, Gudd CLC, Mawhin M-A, et al., 2021, PD-1 blockade improves Kupffer cell bacterial clearance in acute liver injury, Journal of Clinical Investigation, Vol: 131, ISSN: 0021-9738
Pop O-T, Brenig RG, Triantafyllou E, et al., 2020, AXL-expressing homeostatic liver macrophages are reduced in patients with progression of cirrhosis, Publisher: ELSEVIER, Pages: S30-S31, ISSN: 0168-8278
Brenig R, Pop OT, Triantafyllou E, et al., 2020, Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis, Life Science Alliance, Vol: 3, Pages: 1-16, ISSN: 2575-1077
Infectious complications in patients with cirrhosis frequently initiate episodes of decompensation and substantially contribute to the high mortality. Mechanisms of the underlying immuneparesis remain underexplored. TAM receptors (TYRO3/AXL/MERTK) are important inhibitors of innate immune responses. To understand the pathophysiology of immuneparesis in cirrhosis, we detailed TAM receptor expression in relation to monocyte function and disease severity prior to the onset of acute decompensation. TNF-α/IL-6 responses to lipopolysaccharide were attenuated in monocytes from patients with cirrhosis (n = 96) compared with controls (n = 27) and decreased in parallel with disease severity. Concurrently, an AXL-expressing (AXL+) monocyte population expanded. AXL+ cells (CD14+CD16highHLA-DRhigh) were characterised by attenuated TNF-α/IL-6 responses and T cell activation but enhanced efferocytosis and preserved phagocytosis of Escherichia coli. Their expansion correlated with disease severity, complications, infection, and 1-yr mortality. AXL+ monocytes were generated in response to microbial products and efferocytosis in vitro. AXL kinase inhibition and down-regulation reversed attenuated monocyte inflammatory responses in cirrhosis ex vivo. AXL may thus serve as prognostic marker and deserves evaluation as immunotherapeutic target in cirrhosis.
Lebosse F, Gudd C, Tunc E, et al., 2019, CD8+ T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis-associated immune dysfunction, EBioMedicine, Vol: 49, Pages: 258-268, ISSN: 2352-3964
BackgroundCirrhosis-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.MethodsSixty 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™ technology. HLA-DR+CD8+ T cells interactions with PBMCs and myeloid cells were tested in vitro.FindingsPeripheral 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.InterpretationIn patients with cirrhosis, CD8+ T cells display a phenotypic, functional and transcriptional profile which may contribute to CAID.FundThis work was supported by Medical Res
Pop OT, Brenig RG, Triantafyllou E, et al., 2019, AXL-expressing immune-homeostatic liver macrophages disappear in progressive cirrhosis, Publisher: E M H SWISS MEDICAL PUBLISHERS LTD, Pages: 22S-22S, ISSN: 1424-7860
Gudd CLC, Liu T, Triantafyllou E, et al., 2019, Elevated tissue homing of monocytes and increased cytotoxic activity of CD8+T-cells in immune checkpoint inhibitor-induced hepatitis, International Liver Congress / 54th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER, Pages: E19-E20, ISSN: 0168-8278
Triantafyllou E, Gudd C, Nathwani R, et al., 2019, PD-1+monocytes and macrophages contribute to impaired microbial clearance following acute liver failure, International Liver Congress / 54th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER, Pages: E430-E431, ISSN: 0168-8278
McPhail MJW, Trovato F, Triantafyllou E, et al., 2019, Autotaxin mediates lipid dysregulation in acute-on-chronic liver failure, promoting persistence of systemic inflammation via lysophosphatidic acid-mediated monocyte activation, International Liver Congress / 54th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER, Pages: E91-E92, ISSN: 0168-8278
Singanayagam A, Erminelli D, Triantafyllou E, et al., 2019, Immunometabolic profiling of ascites from patients with acute-on-chronic liver failure reveals increased MerTK plus immunosuppressive myeloid cells and cell death markers with preferential lipid metabolism compared to cirrhosis without organ failure, International Liver Congress / 54th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER, Pages: E183-E183, ISSN: 0168-8278
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Triantafyllou E, Woollard K, McPhail M, et al., 2018, The role of monocytes and macrophages in acute and acute-on-chronic liver failure, Frontiers in Immunology, Vol: 9, ISSN: 1664-3224
Acute and acute-on-chronic liver failure (ALF and ACLF), though distinct clinical entities, are considered syndromes of innate immune dysfunction. Patients with ALF and ACLF display evidence of a pro-inflammatory state with local liver inflammation, features of systemic inflammatory response syndrome (SIRS) and vascular endothelial dysfunction that drive progression to multi-organ failure. In an apparent paradox, these patients are concurrently immunosuppressed, exhibiting acquired immune defects that render them highly susceptible to infections. This paradigm of tissue injury succeeded by immunosuppression is seen in other inflammatory conditions such as sepsis, which share poor outcomes and infective complications that account for high morbidity and mortality. Monocyte and macrophage dysfunction are central to disease progression of ALF and ACLF. Activation of liver-resident macrophages (Kupffer cells) by pathogen and damage associated molecular patterns leads to the recruitment of innate effector cells to the injured liver. Early monocyte infiltration may contribute to local tissue destruction during the propagation phase and results in secretion of pro-inflammatory cytokines that drive SIRS. In the hepatic microenvironment, recruited monocytes mature into macrophages following local reprogramming so as to promote resolution responses in a drive to maintain tissue integrity. Intra-hepatic events may affect circulating monocytes through spill over of soluble mediators and exposure to apoptotic cell debris during passage through the liver. Hence, peripheral monocytes show numerous acquired defects in acute liver failure syndromes that impair their anti-microbial programmes and contribute to enhanced susceptibility to sepsis. This review will highlight the cellular and molecular mechanisms by which monocytes and macrophages contribute to the pathophysiology of ALF and ACLF, considering both hepatic inflammation and systemic immunosuppression. We identify areas for f
Brenig R, Pop OT, Perez C, et al., 2018, AXL-expressing immunoregulatory monocytes indicate disease severity in patients with advanced cirrhosis, Publisher: E M H SWISS MEDICAL PUBLISHERS LTD, Pages: 10S-10S, ISSN: 1424-7860
Singanayagam A, Nathwani R, Triantafyllou E, et al., 2018, PLASMA S100A8/A9: A NOVEL MECHANISTIC BIOMARKER IN INNATE IMMUNE ACTIVATION IN ACUTE-ON-CHRONIC LIVER FAILURE, Annual General Meeting of the British-Society-of-Gastroenterology, Publisher: BMJ PUBLISHING GROUP, Pages: A131-A132, ISSN: 0017-5749
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Bernsmeier C, Triantafyllou E, Brenig R, et al., 2018, CD14<sup>+ </sup>CD15<sup>− </sup>HLA-DR<sup>−</sup> myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure, Gut, Vol: 67, Pages: 1155-1167, ISSN: 0017-5749
<jats:sec><jats:title>Objective</jats:title><jats:p>Immune paresis in patients with acute-on-chronic liver failure (ACLF) accounts for infection susceptibility and increased mortality. Immunosuppressive mononuclear CD14<jats:sup>+</jats:sup>HLA-DR<jats:sup>−</jats:sup> myeloid-derived suppressor cells (M-MDSCs) have recently been identified to quell antimicrobial responses in immune-mediated diseases. We sought to delineate the function and derivation of M-MDSC in patients with ACLF, and explore potential targets to augment antimicrobial responses.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Patients with ACLF (n=41) were compared with healthy subjects (n=25) and patients with cirrhosis (n=22) or acute liver failure (n=30). CD14<jats:sup>+</jats:sup>CD15<jats:sup>−</jats:sup>CD11b<jats:sup>+</jats:sup>HLA-DR<jats:sup>−</jats:sup> cells were identified as per definition of M-MDSC and detailed immunophenotypic analyses were performed. Suppression of T cell activation was assessed by mixed lymphocyte reaction. Assessment of innate immune function included cytokine expression in response to Toll-like receptor (TLR-2, TLR-4 and TLR-9) stimulation and phagocytosis assays using flow cytometry and live cell imaging-based techniques.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Circulating CD14<jats:sup>+</jats:sup>CD15<jats:sup>−</jats:sup>CD11b<jats:sup>+</jats:sup>HLA-DR<jats:sup>−</jats:sup> M-MDSCs were markedly expanded in patients with ACLF (55% of CD14+ cells). M-MDSC displayed immunosuppressive properties, significantly decreasing T cell proliferation (p=0.01), producing less tumour necrosis factor-alpha/interleukin-6 in response to TLR stimulation (all p<0.01), and redu
Kumar N, Khamri W, Sadiq F, et al., 2018, Circulating NK cells in cirrhosis are hypofunctional, with an expanded inhibitory liver-homing CD56dimCD16+/- NK cell population, International Liver Congress (ILC), Publisher: ELSEVIER SCIENCE BV, Pages: S611-S611, ISSN: 0168-8278
Brenig R, Perez C, Duong FHT, et al., 2018, AXL-expressing monocytes indicate immuneparesis and disease severity in patients with cirrhosis, International Liver Congress (ILC), Publisher: ELSEVIER SCIENCE BV, Pages: S613-S613, ISSN: 0168-8278
Triantafyllou E, Pop O, Possamai L, et al., 2017, MERTK EXPRESSING HEPATIC MACROPHAGES PROMOTE THE RESOLUTION OF INFLAMMATION IN ACUTE LIVER FAILURE, Annual General Meeting of the British-Society-of-Gastroenterology (BSG), Publisher: BMJ PUBLISHING GROUP, Pages: A48-A49, ISSN: 0017-5749
Khamri W, Abeles RD, Hou TZ, et al., 2017, Increased Expression of Cytotoxic T-Lymphocyte−Associated Protein 4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure, Gastroenterology, Vol: 153, Pages: 263-276.e8, ISSN: 0016-5085
Triantafyllou E, Pop O, Possamai L, et al., 2017, MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure, Gut, Vol: 67, Pages: 333-347, ISSN: 1468-3288
Objective Acute liver failure (ALF) is characterised by overwhelming hepatocyte death and liver inflammation with massive infiltration of myeloid cells in necrotic areas. The mechanisms underlying resolution of acute hepatic inflammation are largely unknown. Here, we aimed to investigate the impact of Mer tyrosine kinase (MerTK) during ALF and also examine how the microenvironmental mediator, secretory leucocyte protease inhibitor (SLPI), governs this response.Design Flow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotype, functional/transcriptomic profile and tissue topography of MerTK+ monocytes/macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer−/−) mice. SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice.Results We demonstrate a significant expansion of resolution-like MerTK+HLA-DRhigh cells in circulatory and tissue compartments of patients with ALF. Compared with WT mice which show an increase of MerTK+MHCIIhigh macrophages during the resolution phase in ALF, APAP-treated Mer−/− mice exhibit persistent liver injury and inflammation, characterised by a decreased proportion of resident Kupffer cells and increased number of neutrophils. Both in vitro and in APAP-treated mice, SLPI reprogrammes myeloid cells towards resolution responses through induction of a MerTK+HLA-DRhigh phenotype which promotes neutrophil apoptosis and their subsequent clearance.Conclusions We identify a hepatoprotective, MerTK+, macrophage phenotype that evolves during the resolution phase following ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury.
Mukherjee S, Pop O, Triantafyllou E, et al., 2017, Role of expression of the tumour-associated macrophage receptor, MERTK, in hepatocellular carcinoma, Spring Meeting on Clinician Scientists in Training, Publisher: ELSEVIER SCIENCE INC, Pages: 72-72, ISSN: 0140-6736
McPhail MJW, Shawcross D, Lewis MR, et al., 2016, Mutlivariate metabotyping of plasma accurately predicts survival in decompensated cirrhosis, Journal of Hepatology, Vol: 64, Pages: 1058-1067, ISSN: 1600-0641
Background & AimsPredicting survival in decompensated cirrhosis (DC) is important in decision making for liver transplantation and resource allocation. We investigated whether high-resolution metabolic profiling can determine a metabolic phenotype associated with 90-day survival.MethodsTwo hundred and forty-eight subjects underwent plasma metabotyping by 1H nuclear magnetic resonance (NMR) spectroscopy and reversed-phase ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC-TOF-MS; DC: 80-derivation set, 101-validation; stable cirrhosis (CLD) 20 and 47 healthy controls (HC)).Results1H NMR metabotyping accurately discriminated between surviving and non-surviving patients with DC. The NMR plasma profiles of non-survivors were attributed to reduced phosphatidylcholines and lipid resonances, with increased lactate, tyrosine, methionine and phenylalanine signal intensities. This was confirmed on external validation (area under the receiver operating curve [AUROC] = 0.96 (95% CI 0.90–1.00, sensitivity 98%, specificity 89%). UPLC-TOF-MS confirmed that lysophosphatidylcholines and phosphatidylcholines [LPC/PC] were downregulated in non-survivors (UPLC-TOF-MS profiles AUROC of 0.94 (95% CI 0.89–0.98, sensitivity 100%, specificity 85% [positive ion detection])). LPC concentrations negatively correlated with circulating markers of cell death (M30 and M65) levels in DC. Histological examination of liver tissue from DC patients confirmed increased hepatocyte cell death compared to controls. Cross liver sampling at time of liver transplantation demonstrated that hepatic endothelial beds are a source of increased circulating total cytokeratin-18 in DC.ConclusionPlasma metabotyping accurately predicts mortality in DC. LPC and amino acid dysregulation is associated with increased mortality and severity of disease reflecting hepatocyte cell death.
Larsen FS, Schmidt LE, Bernsmeier C, et al., 2016, High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial, Journal of Hepatology, Vol: 64, Pages: 69-78, ISSN: 0168-8278
Singanayagam A, Triantafyllou E, Patel VC, et al., 2016, MER TYROSINE KINASE REGULATES THE ACTIVATION OF MYELOID CELLS AND INNATE IMMUNE RESPONSES IN ACUTE-ON-CHRONIC LIVER FAILURE, EASL International Liver Congress, Publisher: ELSEVIER SCIENCE BV, Pages: S143-S143, ISSN: 0168-8278
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Purswani S, Reynolds G, Liu Y, et al., 2016, HUMAN LIVER EXPLANTS HAVE ENRICHED PRO-INFLAMMATORY CD24-B CELL POPULATIONS, EASL International Liver Congress, Publisher: ELSEVIER SCIENCE BV, Pages: S530-S530, ISSN: 0168-8278
Mukherjee SK, Pop OT, Triantafyllou E, et al., 2016, MER TYROSINE KINASE POSITIVE TUMOUR ASSOCIATED MACROPHAGES ARE A NOVEL THERAPEUTIC TARGET IN HEPATOCELLULAR CARCINOMA, EASL International Liver Congress, Publisher: ELSEVIER SCIENCE BV, Pages: S574-S575, ISSN: 0168-8278
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Triantafyllou E, Wilhelm A, Possamai L, et al., 2016, SECRETORY LEUKOCYTE PROTEASE INHIBITOR DRIVES HEPATIC RESOLUTION RESPONSES IN ACUTE LIVER FAILURE THROUGH MODULATION OF THE MER TYROSINE KINASE PATHWAY, EASL International Liver Congress, Publisher: ELSEVIER SCIENCE BV, Pages: S512-S512, ISSN: 0168-8278
Triantafyllou E, Liaskou E, Khamri W, et al., 2015, SECRETORY LEUKOCYTE PROTEASE INHIBITOR (SLPI) SUPPRESSES INNATE IMMUNE RESPONSES AND PROMOTES RESOLUTION OF INFLAMMATION IN AN AUTO/PARACRINE MANNER DURING ACUTE LIVER FAILURE (ALF), 50th International Liver Congress of the European-Association-for-the-Study-of-the-Liver, Publisher: ELSEVIER SCIENCE BV, Pages: S500-S501, ISSN: 0168-8278
Bernsmeier C, Tidswell R, Ghataore L, et al., 2015, PROOF-OF-PRINCIPLE EVALUATION OF IMMUNOMODULATORY DRUGS IN PROMOTING PHAGOCYTOSIS CAPACITY IN PATIENTS WITH LIVER FAILURE, 50th International Liver Congress of the European-Association-for-the-Study-of-the-Liver, Publisher: ELSEVIER SCIENCE BV, Pages: S324-S324, ISSN: 0168-8278
Parker R, Weston C, Possamai LA, et al., 2015, CCR9 AND CCL25 ARE EARLY PRO-INFLAMMATORY MEDIATORS IN ACUTE LIVER INJURY, 50th International Liver Congress of the European-Association-for-the-Study-of-the-Liver, Publisher: ELSEVIER SCIENCE BV, Pages: S206-S207, ISSN: 0168-8278
Bernsmeier C, Pop OT, Singanayagam A, et al., 2015, Patients With Acute-on-Chronic Liver Failure Have Increased Numbers of Regulatory Immune Cells Expressing the Receptor Tyrosine Kinase MERTK, Gastroenterology, Vol: 148, Pages: 603-615.e14, ISSN: 0016-5085
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