110 results found
Siggins MK, Lynskey NN, Lamb L, et al., 2020, Extracellular bacterial lymphatic metastasis drives Streptococcus pyogenes systemic infection, Nature Communications, Vol: 11, ISSN: 2041-1723
Unassisted metastasis through the lymphatic system is a mechanism of dissemination thus far ascribed only to cancer cells. Here, we report that Streptococcus pyogenes also hijack lymphatic vessels to escape a local infection site, transiting through sequential lymph nodes and efferent lymphatic vessels to enter the bloodstream. Contrasting with previously reported mechanisms of intracellular pathogen carriage by phagocytes, we show S. pyogenes remain extracellular during transit, first in afferent and then efferent lymphatics that carry the bacteria through successive draining lymph nodes. We identify streptococcal virulence mechanisms important for bacterial lymphatic dissemination and show that metastatic streptococci within infected lymph nodes resist and subvert clearance by phagocytes, enabling replication that can seed intense bloodstream infection. The findings establish the lymphatic system as both a survival niche and conduit to the bloodstream for S. pyogenes, explaining the phenomenon of occult bacteraemia. This work provides new perspectives in streptococcal pathogenesis with implications for immunity.
Turner-Stokes T, Garcia Diaz A, Pinheiro D, et al., 2020, Live imaging of monocyte subsets in immune complex-mediated glomerulonephritis reveals distinct phenotypes and effector functions., Journal of the American Society of Nephrology, Vol: 31, Pages: 1-1, ISSN: 1046-6673
BACKGROUND: Immune complexes within glomerular capillary walls cause crescentic GN (CrGN). Monocytes and macrophages are important in mediating CrGN, but little work has been done to phenotype the subpopulations involved and determine their respective contributions to glomerular inflammation. METHODS: Live glomerular imaging using confocal microscopy monitored intravascular monocyte subset behavior during nephrotoxic nephritis (NTN) in a novel WKY-hCD68-GFP monocyte/macrophage reporter rat strain. Flow cytometry and qPCR further analyzed ex vivo the glomerular leukocyte infiltrate during NTN. RESULTS: Non-classical monocytes surveyed the glomerular endothelium via lymphocyte function-associated antigen 1 (LFA-1) in the steady state. During NTN, non-classical monocytes were recruited first, but subsequent recruitment and retention of classical monocytes was associated with glomerular damage. Monocytes recruited to the glomerular vasculature did not undergo transendothelial migration. This finding suggests that inflammation in immune complex-mediated CrGN is predominantly intravascular, driven by dynamic interactions between intravascular blood monocytes and the endothelium. Glomerular endothelium and non-classical monocytes overexpressed a distinct chemokine axis, which may orchestrate inflammatory myeloid cell recruitment and expression of damage mediators. Reduced classical monocyte recruitment in Lewis rats during NTN confirmed a role for CD16 in mediating glomerular damage. CONCLUSIONS: Monocyte subsets with distinct phenotypes and effector functions may be important in driving inflammation in experimental CrGN resulting from immune complexes formed within the glomerular capillary wall. LFA-1-dependent endothelial surveillance by non-classical monocytes may detect immune complexes through CD16, orchestrating the inflammatory response through intravascular retention of classical monocytes, which results in glomerular damage and proteinuria.
Srivatsan A, Woollard K, 2020, Immunohistologic comparison and thrombus NET analysis in stroke and myocardial infarction, Neurology, Vol: 94, Pages: 955-956, ISSN: 0028-3878
Ye X, Bright R, Woollard K, et al., 2020, MONOCYTE/NEUTROPHIL: LYMPHOCYTE RATIO, C-REACTIVE PROTEIN IN THE LAST YEAR BEFORE DEATH IN DIFFERENT VINTAGE GROUPS - RESULTS FROM THE MONDO INITIATIVE, 57th ERA-EDTA Congress, Publisher: OXFORD UNIV PRESS, Pages: 1765-1765, ISSN: 0931-0509
Bright R, Ye X, Woollard K, et al., 2020, MONOCYTE-TO-LYMPHOCYTE RATIO, AN INDEPENDENT RISK FACTOR OF SURVIVAL IN HEMODIALYSIS PATIENTS: RESULTS FROM THE INTERNATIONAL MONDO CONSORTIUM, 57th ERA-EDTA Congress, Publisher: OXFORD UNIV PRESS, Pages: 66-66, ISSN: 0931-0509
Constantinescu-Bercu A, Grassi L, Frontini M, et al., 2020, Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2., eLife, Vol: 9, ISSN: 2050-084X
Platelet-neutrophil interactions are important for innate immunity, but also contribute to the pathogenesis of deep vein thrombosis, myocardial infarction and stroke. Here we report that, under flow, von Willebrand factor/glycoprotein Iba-dependent platelet 'priming' induces integrin aIIbb3 activation that, in turn, mediates neutrophil and T-cell binding. Binding of platelet aIIbb3 to SLC44A2 on neutrophils leads to mechanosensitive-dependent production of highly prothrombotic neutrophil extracellular traps. A polymorphism in SLC44A2 (rs2288904-A) present in 22% of the population causes an R154Q substitution in an extracellular loop of SLC44A2 that is protective against venous thrombosis results in severely impaired binding to both activated aIIbb3 and VWF-primed platelets. This was confirmed using neutrophils homozygous for the SLC44A2 R154Q polymorphism. Taken together, these data reveal a previously unreported mode of platelet-neutrophil crosstalk, mechanosensitive NET production, and provide mechanistic insight into the protective effect of the SLC44A2 rs2288904-A polymorphism in venous thrombosis.
Hill N, Michell DL, Ramirez-Solano M, et al., 2020, Glomerular endothelial derived vesicles mediate podocyte dysfunction: A potential role for miRNA, PLoS One, Vol: 15, ISSN: 1932-6203
MicroRNAs (miRNA) are shown to be involved in the progression of several types of kidney diseases. Podocytes maintain the integrity of the glomerular basement membrane. Extracellular vesicles (EV) are important in cell-to-cell communication as they can transfer cellular content between cells, including miRNA. However, little is known about how extracellular signals from the glomerular microenvironment regulate podocyte activity. Using a non-contact transwell system, communication between glomerular endothelial cells (GEnC) and podocytes was characterised in-vitro. Identification of transferred EV-miRNAs from GEnC to podocytes was performed using fluorescence cell tracking and miRNA mimetics. To represent kidney disease, podocyte molecular profiling and functions were analysed after EV treatments derived from steady state or activated GEnC. Our data shows activation of GEnC alters EV-miRNA loading, but activation was not found to alter EV secretion. EV delivery of miRNA to recipient podocytes altered cellular miRNA abundance and effector functions in podocytes, including decreased secretion of VEGF and increased mitochondrial stress which lead to altered cellular metabolism and cytoskeletal rearrangement. Finally, results support our hypothesis that miRNA-200c-3p is transfered by EVs from GEnC to podocytes in response to activation, ultimately leading to podocyte dysfunction.
Lai YC, Woollard KJ, McClelland RL, et al., 2019, The association of plasma lipids with white blood cell counts: Results from the Multi-Ethnic Study of Atherosclerosis, JOURNAL OF CLINICAL LIPIDOLOGY, Vol: 13, Pages: 812-820, ISSN: 1933-2874
Rahman MS, Vorkas P, Frost G, et al., 2019, OUTLINING THE HUMAN MONOCYTE INFLAMMATORY CYTOKINE RESPONSE TO DIETARY FAT INTAKE, Annual Conference of the British-Cardiovascular-Society (BCS) - Digital Health Revolution, Publisher: BMJ PUBLISHING GROUP, Pages: A159-A160, ISSN: 1355-6037
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
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
Prendecki M, Mcadoo S, Turner-Stokes T, et al., 2019, A NOVEL P2X7 KNOCKOUT RAT IS NOT PROTECTED FROM EXPERIMENTAL GLOMERULONEPHRITIS OR VASCULITIS, 19th International Vasculitis and ANCA Workshop, Publisher: OXFORD UNIV PRESS, ISSN: 1462-0324
Prendecki M, Mcadoo S, Turner-Stokes T, et al., 2019, THE EFFECT OF P2X7 ANTAGONISM ON NEPHROTOXIC NEPHRITIS, 19th International Vasculitis and ANCA Workshop, Publisher: OXFORD UNIV PRESS, Pages: 93-94, ISSN: 1462-0324
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
Saja M, Cook HT, Ruseva M, et al., 2018, A triglyceride-rich lipoprotein environment exacerbates renal injury in the accelerated nephrotoxic nephritis model, Clinical and Experimental Immunology, Vol: 192, Pages: 337-347, ISSN: 1365-2249
Hyperlipidaemia accompanies chronic renal disease either as a consequence of the renal dysfunction or as part of generalized metabolic derangements. Under both situations, the lipid profile is characterized by accumulation of triglyceride‐rich lipoproteins (TGRLs). This lipid profile is recognized as a risk factor for cardiovascular complications. Whether it may pose a risk for renal injury as well remains unclear. A hyper‐TGRL state was generated in C57BL/6 mice using poloxamer‐407 (P‐407) and immune complex‐mediated renal injury was triggered using the accelerated nephrotoxic nephritis (ANTN) model. The hyper‐TGRL animals were hypersensitive to ANTN demonstrated by greater haematuria and glomerular cellularity. These changes were accompanied by increased glomerular accumulation of CD68+ macrophages. The hypersensitive response to ANTN was not seen in low‐density lipoprotein receptor knock‐out mice fed with a high fat diet, where triglyceride levels were lower but cholesterol levels comparable to those obtained using P‐407. These data indicate that a hyper‐TGRL state might be more detrimental to the kidneys than low‐density lipoprotein‐driven hypercholesterolaemia during immune complex‐mediated nephritis. We speculate that the hyper‐TGRL environment primes the kidney to exacerbated renal damage following an inflammatory insult with increased accumulation of macrophages that may play a key role in mediating the injurious effects.
Cochran BJ, Pinheiro D, Prendecki M, et al., 2018, PRO-ATHEROSCLEROTIC LOW-DENSITY NEUTROPHILS ARE PRESENT IN HYPERCHOLESTEROLEMIA, International Symposium on Atherosclerosis (ISA), Publisher: ELSEVIER IRELAND LTD, Pages: 39-40, ISSN: 1567-5688
Cochran BJ, Pinheiro D, Prendecki M, et al., 2018, Pro-atherosclerotic Low-density Neutrophils Are Present in Hypercholesterolemia, Scientific Sessions of the American-Heart-Association on Vascular Discovery - From Genes to Medicine, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 1079-5642
Woollard KJ, Murphy AJ, 2017, The Endless Summer Thermoneutrality Prevents Monocytosis and Reduces Atherosclerosis, Circulation Research, Vol: 121, Pages: 596-598, ISSN: 0009-7330
Rahman S, Vorkas P, Morrison D, et al., 2017, ACUTE DIETARY SATURATED FAT INTAKE CAN SUPPRESS THE INFLAMMATORY RESPONSE IN HUMAN CIRCULATING FOAMY MONOCYTES, 85th Congress of the European-Atherosclerosis-Society (EAS), Publisher: Elsevier, Pages: E116-E116, ISSN: 0021-9150
Woollard K, Jackson W, Baudino L, et al., 2017, ELEVATED TRIGLYCERIDES PROMOTE THE EXTRAVASATION AND TISSUE RETENTION OF MONOCYTE SUBSETS, 85th Congress of the European-Atherosclerosis-Society (EAS), Publisher: ELSEVIER IRELAND LTD, Pages: E9-E9, ISSN: 0021-9150
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
Diaz AIG, Vloumidi E, Sardini A, et al., 2017, Cardiac macrophage infiltration during chronic kidney disease accelerates cardiovascular disease, Annual Conference of the British-Cardiovascular-Society (BCS), Publisher: BMJ PUBLISHING GROUP, Pages: A141-A142, ISSN: 1355-6037
Rahman MS, Woollard K, 2017, Atherosclerosis., The Immunology of Cardiovascular Homeostasis and Pathology, Editors: Sattler, Kennedy-Lydon, Publisher: Springer, Pages: 121-144, ISBN: 978-3-319-57613-8
In this chapter, we discuss the manner through which the immune system regulates the cardiovascular system in health and disease. We define the cardiovascular system and elements of atherosclerotic disease, the main focus in this chapter. Herein we elaborate on the disease process that can result in myocardial infarction (heart attack), ischaemic stroke and peripheral arterial disease. We have discussed broadly the homeostatic mechanisms in place that help autoregulate the cardiovascular system including the vital role of cholesterol and lipid clearance as well as the role lipid homeostasis plays in cardiovascular disease in the context of atherosclerosis. We then elaborate on the role played by the immune system in this setting, namely, major players from the innate and adaptive immune system, as well as discussing in greater detail specifically the role played by monocytes and macrophages.This chapter should represent an overview of the role played by the immune system in cardiovascular homeostasis; however further reading of the references cited can expand the reader's knowledge of the detail, and we point readers to many excellent reviews which summarise individual immune systems and their role in cardiovascular disease.
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.
Rahman MS, Murphy AJ, Woollard KJ, 2017, Effects of dyslipidaemia on monocyte production and function in cardiovascular disease., Nature Reviews Cardiology, Vol: 14, Pages: 387-400, ISSN: 1759-5010
Monocytes are heterogeneous effector cells involved in the maintenance and restoration of tissue integrity. Monocytes and macrophages are involved in cardiovascular disease progression, and are associated with the development of unstable atherosclerotic plaques. Hyperlipidaemia can accelerate cardiovascular disease progression. However, monocyte responses to hyperlipidaemia are poorly understood. In the past decade, accumulating data describe the relationship between the dynamic blood lipid environment and the heterogeneous circulating monocyte pool, which might have profound consequences for cardiovascular disease. In this Review, we explore the updated view of monocytes in cardiovascular disease and their relationship with macrophages in promoting the homeostatic and inflammatory responses related to atherosclerosis. We describe the different definitions of dyslipidaemia, highlight current theories on the ontogeny of monocyte heterogeneity, discuss how dyslipidaemia might alter monocyte production, and explore the mechanistic interface linking dyslipidaemia with monocyte effector functions, such as migration and the inflammatory response. Finally, we discuss the role of dietary and endogenous lipid species in mediating dyslipidaemic responses, and the role of these lipids in promoting the risk of cardiovascular disease through modulation of monocyte behaviour.
Woollard KJ, 2016, The immune system in cardiovascular pathology, The Immunology of Cardiovascular Homeostasis and Pathology
Lee M, Woollard K, Henstridge D, et al., 2016, Increased glycolytic capacity in CD16(+) monocyte subset-derived M2 macrophages is linked to foam cell formation, International Congress of Immunology (ICI), Publisher: WILEY-BLACKWELL, Pages: 837-837, ISSN: 0014-2980
Diaz AIG, Moyon B, Coan PM, et al., 2016, New Wistar Kyoto and spontaneously hypertensive rat transgenic models with ubiquitous expression of green fluorescent protein, Disease Models & Mechanisms, Vol: 9, Pages: 463-471, ISSN: 1754-8411
The Wistar Kyoto (WKY) rat and the spontaneously hypertensive (SHR) rat inbred strains are well-established models for human crescentic glomerulonephritis (CRGN) and metabolic syndrome, respectively. Novel transgenic (Tg) strains add research opportunities and increase scientific value to well-established rat models. We have created two novel Tg strains using Sleeping Beauty transposon germline transgenesis, ubiquitously expressing green fluorescent protein (GFP) under the rat elongation factor 1 alpha (EF1a) promoter on the WKY and SHR genetic backgrounds. The Sleeping Beauty system functioned with high transgenesis efficiency; 75% of new rats born after embryo microinjections were transgene positive. By ligation-mediated PCR, we located the genome integration sites, confirming no exonic disruption and defining a single or low copy number of the transgenes in the new WKY-GFP and SHR-GFP Tg lines. We report GFP-bright expression in embryos, tissues and organs in both lines and show preliminary in vitro and in vivo imaging data that demonstrate the utility of the new GFP-expressing lines for adoptive transfer, transplantation and fate mapping studies of CRGN, metabolic syndrome and other traits for which these strains have been extensively studied over the past four decades.
Khamis RY, Woollard K, Kojima C, et al., 2016, A NOVEL IGG AUTOANTIBODY, LO9, REACTS SPECIFICALLY WITH ADHERENT LOW DENSITY LIPOPROTEIN (LDL), TARGETS LDL IN ATHEROSCLEROSIS IN VIVO AND STIMULATES MACROPHAGE TNFα RELEASE, Publisher: Elsevier, Pages: 2324-2324, ISSN: 1558-3597
Khamis RY, Woollard KJ, Hyde GD, et al., 2016, Near Infrared Fluorescence (NIRF) Molecular Imaging of Oxidized LDL with an Autoantibody in Experimental Atherosclerosis, Scientific Reports, Vol: 6, ISSN: 2045-2322
We aimed to develop a quantitative antibody-based near infrared fluorescence (NIRF) approachfor the imaging of oxidized LDL in atherosclerosis. LO1, a well- characterized monoclonalautoantibody that reacts with malondialdehyde-conjugated LDL, was labeled with a NIRF dye toyield LO1-750. LO1-750 specifically identified necrotic core in ex vivo human coronary lesions.Injection of LO1-750 into high fat (HF) fed atherosclerotic Ldlr-/-mice led to specific focallocalization within the aortic arch and its branches, as detected by fluorescence moleculartomography (FMT) combined with micro-computed tomography (CT). Ex vivo confocalmicroscopy confirmed LO1-750 subendothelial localization of LO1-750 at sites ofatherosclerosis, in the vicinity of macrophages. When compared with a NIRF reporter of MMPactivity (MMPSense-645-FAST), both probes produced statistically significant increases inNIRF signal in the Ldlr-/- model in relation to duration of HF diet. When withdrawing the HFdiet, the reduction in oxLDL accumulation, as demonstrated with LO1-750, was less markedthan the effect seen on MMP activity. In the rabbit, in vivo injected LO1-750 localization wassuccessfully imaged ex vivo in aortic lesions with a customised intra-arterial NIRF detectioncatheter. A partially humanized chimeric LO1-Fab-Cys localized similarly to the parentantibody in murine atheroma showing promise for future translation.
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