121 results found
Possamai L, Gudd C, Au L, et al., 2021, Activation and transcriptional profile of monocytes and CD8+ T cells are altered in checkpoint inhibitor-related hepatitis, Journal of Hepatology, Vol: 75, Pages: 177-189, ISSN: 0168-8278
Background & Aims: Checkpoint inhibitor-related hepatitis (CPI-Hep) is an emerging clinical challenge. We aimed to gain insights into the immunopathology of CPI-Hep by comprehensively characterising myeloid and lymphoid subsets.Methods: CPI-treated patients with or without related hepatitis (CPI-Hep; n = 22 and CPI-noHep; n = 7) were recruited. Phenotypic and transcriptional profiling of peripheral immune subsets was performed and compared with 19 healthy controls (HCs). In vitro monocyte-derived macrophages (MoMFs) were assessed for activation and cytokine production. CD163, CCR2, CD68, CD3, CD8 and granzyme B expression was assessed using immunohistochemistry/immunofluorescence (n = 4).Results: A significant total monocyte depletion was observed in CPI-Hep compared with HCs (p = 0.04), along with a proportionate increase in the classical monocyte population (p = 0.0002) and significant upregulation of CCR2, CD163 and downregulation of CCR7. Soluble CD163 levels were significantly elevated in CPI-Hep compared with HCs (p <0.0001). In vitro MoMFs from CPI-Hep showed enhanced production of pro-inflammatory cytokines. CD8+ T cells demonstrated increased perforin, granzyme B, ICOS and HLA-DR expression in CPI-Hep. Transcriptional profiling indicated the presence of activated monocyte and enhanced effector CD8+ T cell populations in CPI-Hep. Immunohistochemistry demonstrated co-localisation of CD8+/granzyme B+ T cells with CD68+CCR2+/CD68+CD163+ macrophages in CPI-Hep liver tissue.Conclusions: CPI-Hep is associated with activation of peripheral monocytes and an enhanced cytotoxic, effector CD8+ T cell phenotype. These changes were reflected by liver inflammation composed of CD163+/CCR2+ macrophages and CD8+ T cells.Lay summary: Some patients who receive immunotherapy for cancer develop liver inflammation, which requires cessation of cancer treatment. Herein, we describe ways in which the white blood cells of patients who develop liver inflammation differ from tho
Constantinescu-Bercu A, Wang YA, Woollard KJ, et al., 2021, The GPIbα intracellular tail – role in transducing VWF- and collagen/GPVI-mediated signaling, Haematologica, ISSN: 0390-6078
<jats:p>The GPIbT-VWF A1 domain interaction is essential for platelet tethering under high shear. Synergy between GPIbα and GPVI signaling machineries has been suggested previously, however its molecular mechanism remains unclear. We generated a novel GPIbα transgenic mouse (GpIbαΔsig/Δsig) by CRISPR-Cas9 technology to delete the last 24 residues of the GPIbα intracellular tail that harbors the 14-3-3 and phosphoinositide-3 kinase binding sites. GPIbαΔsig/Δsig platelets bound VWF normally under flow. However, they formed fewer filopodia on VWF/botrocetin in the presence of a oIIbI3 blocker, demonstrating that despite normal ligand binding, VWF-dependent signaling is diminished. Activation of GpIbαΔsig/Δsig platelets with ADP and thrombin was normal, but GpIbαΔsig/Δsig platelets stimulated with collagen-related-peptide (CRP) exhibited markedly decreased P-selectin exposure and eIIbI3 activation, suggesting a role for the GpIbaaintracellular tail in GPVI-mediated signaling. Consistent with this, while haemostasis was normal in GPIbαΔsig/Δsig mice, diminished tyrosine-phosphorylation, (particularly pSYK) was detected in CRP-stimulated GpIbαΔsig/Δsig platelets as well as reduced platelet spreading on CRP. Platelet responses to rhodocytin were also affected in GpIbαΔsig/Δsig platelets but to a lesser extent than those with CRP. GpIbαΔsig/Δsig platelets formed smaller aggregates than wild-type platelets on collagen-coated microchannels at low, medium and high shear. In response to both VWF and collagen binding, flow assays performed with plasma-free blood or in the presence of bIIbI3- or GPVI-blockers suggested reduced bIIbI3 activation contributes to the phenotype of the GpIbαΔsig/Δsig platelets. Together, these results reveal a new role for the intracellular tail of GPIbiiin transducing
Prendecki M, Gulati K, Turner-Stokes T, et al., 2021, Characterisation of an enhanced preclinical model of experimental MPO-ANCA autoimmune vasculitis, Journal of Pathology, ISSN: 0022-3417
Experimental autoimmune vasculitis (EAV) is a model of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) induced by immunisation of susceptible rat strains with myeloperoxidase (MPO). Animals develop circulating MPO-ANCA, pulmonary haemorrhage and glomerulonephritis, although renal injury is mild and recovers spontaneously without treatment. In this study we aimed to augment the severity of glomerulonephritis. Following induction of EAV on day 0, a sub-nephritogenic dose of nephrotoxic serum (NTS) containing heterologous antibodies to glomerular basement membrane was administered on day 14. This resulted in a significant increase in disease severity at day 28 compared to MPO immunisation alone - with more urinary abnormalities, infiltrating glomerular leucocytes, and crescent formation that progressed to glomerular and tubulointerstitial scarring by day 56, recapitulating important features of human disease. Importantly, the glomerulonephritis remained pauci-immune, and was strictly dependent on the presence of autoimmunity to MPO, as there was no evidence of renal disease following administration of sub-nephritogenic NTS alone or after immunisation with a control protein in place of MPO. Detailed phenotyping of glomerular leucocytes identified an early infiltrate of non-classical monocytes following NTS administration that, in the presence of autoimmunity to MPO, may initiate the subsequent influx of classical monocytes which augment glomerular injury. We also showed that this model can be used to test novel therapeutics by using a small molecule kinase inhibitor (fostamatinib) that rapidly attenuated both glomerular and pulmonary injury over a four-day treatment period. We believe that this enhanced model of MPO-AAV will prove useful for the study of glomerular leucocyte behaviour and novel therapeutics in AAV in the future. This article is protected by copyright. All rights reserved.
George MJ, Jasmin NH, Cummings VT, et al., 2021, Selective interleukin-6 trans-signaling blockade is more effective than panantagonism in reperfused myocardial infarction, JACC: Basic to Translational Science, Vol: 6, Pages: 431-443, ISSN: 2452-302X
Interleukin (IL)-6 is an emerging therapeutic target in myocardial infarction (MI). IL-6 has 2 distinct signaling pathways: trans-signaling, which mediates inflammation, and classic signaling, which also has anti-inflammatory effects. The novel recombinant fusion protein sgp130Fc achieves exclusive trans-signaling blockade, whereas anti-IL-6 antibodies (Abs) result in panantagonism. In a rat model of reperfused MI, sgp130Fc, but not anti-IL-6-Ab, attenuated neutrophil and macrophage infiltration into the myocardium, reduced infarct size, and preserved cardiac function 28 days after MI. These data demonstrate the efficacy of exclusive IL-6 trans-signaling blockade and support further investigation of sgp130Fc as a potential novel therapy in MI.
Kiefer J, Zeller J, Bogner B, et al., 2021, An unbiased flow cytometry-based approach to assess subset-specific circulating monocyte activation and cytokine profile in whole blood., Frontiers in Immunology, Vol: 12, ISSN: 1664-3224
Monocytes are the third most frequent type of leukocytes in humans, linking innate and adaptive immunity and are critical drivers in many inflammatory diseases. Based on the differential expression of surface antigens, three monocytic subpopulations have been suggested in humans and two in rats with varying inflammatory and phenotype characteristics. Potential intervention strategies that aim to manipulate these cells require an in-depth understanding of monocyte behavior under different conditions. However, monocytes are highly sensitive to their specific activation state and expression of surface markers, which can change during cell isolation and purification. Thus, there is an urgent need for an unbiased functional analysis of activation in monocyte subtypes, which is not affected by the isolation procedure. Here, we present a flow cytometry-based protocol for evaluating subset-specific activation and cytokine expression of circulating blood monocytes both in humans and rats using small whole blood samples (50 - 100 μL). In contrast to previously described monocyte isolation and flow cytometry visualization methods, the presented approach virtually leaves monocyte subsets in a resting state or fixes them in their current state and allows for an unbiased functional endpoint analysis without prior cell isolation. This protocol is a comprehensive tool for studying differential monocyte regulation in the inflammatory and allogeneic immune response in vitro and vivo.
Michell DL, Shihata WA, Andrews KL, et al., 2021, High intraluminal pressure promotes vascular inflammation via caveolin-1, Scientific Reports, Vol: 11, Pages: 1-15, ISSN: 2045-2322
The aetiology and progression of hypertension involves various endogenous systems, such as the renin angiotensin system, the sympathetic nervous system, and endothelial dysfunction. Recent data suggest that vascular inflammation may also play a key role in the pathogenesis of hypertension. This study sought to determine whether high intraluminal pressure results in vascular inflammation. Leukocyte adhesion was assessed in rat carotid arteries exposed to 1 h of high intraluminal pressure. The effect of intraluminal pressure on signaling mechanisms including reactive oxygen species production (ROS), arginase expression, and NFĸB translocation was monitored. 1 h exposure to high intraluminal pressure (120 mmHg) resulted in increased leukocyte adhesion and inflammatory gene expression in rat carotid arteries. High intraluminal pressure also resulted in a downstream signaling cascade of ROS production, arginase expression, and NFĸB translocation. This process was found to be angiotensin II-independent and mediated by the mechanosensor caveolae, as caveolin-1 (Cav1)-deficient endothelial cells and mice were protected from pressure-induced vascular inflammatory signaling and leukocyte adhesion. Cav1 deficiency also resulted in a reduction in pressure-induced glomerular macrophage infiltration in vivo. These findings demonstrate Cav1 is an important mechanosensor in pressure-induced vascular and renal inflammation.
Constantinescu-Bercu A, Wang YA, Woollard K, et al., 2020, The GPIbα intracellular tail - role in transducing VWF- and Collagen/GPVI-mediated signaling, Publisher: Cold Spring Harbor Laboratory
Synergy between GPIbα and GPVI signaling machineries has been suggested previously, however its molecular mechanism remains unclear. We generated a novel GPIbα transgenic mouse (GPIbαΔsig/Δsig) by CRISPR-Cas9 technology to delete the last 24 residues of the GPIbα intracellular tail important for VWF-mediated signaling. GPIbαΔsig/Δsig platelets bound VWF normally under flow but formed fewer filopodia on VWF/botrocetin, demonstrating that the deleted region does not affect ligand binding but appreciably impairs VWF-dependent signaling. Notably, while haemostasis was normal in GPIbαΔsig/Δsig mice, GPIbαΔsig/Δsig platelets exhibited defective responses after collagen-related-peptide stimulation and formed smaller aggregates on collagen-coated microchannels at low and high shears. Flow assays performed with plasma-free blood or in the presence of αIIbβ3-or GPVI-blockers suggested reduced αIIbβ3 activation contributes to the phenotype of the GPIbαΔsig/Δsig platelets. Together, these results reveal a new role for the intracellular tail of GPIbα in transducing both VWF-GPIbα and collagen-GPVI signaling events in platelets.
Triantafyllou E, Gudd C, Mawhin M-A, et al., 2020, PD-1 blockade improves Kupffer cell bacterial clearance in acute liver injury, Journal of Clinical Investigation, Vol: 131, Pages: 1-16, ISSN: 0021-9738
Acute liver failure (ALF) patients display systemic innate immune suppression and increased susceptibility to infections. PD-1 expression by macrophages has been associated with immune suppression during sepsis and cancer. We therefore examined the role of PD-1/PD-L1 pathway in regulating Kupffer cell inflammatory and antimicrobial responses in acetaminophen (APAP) induced acute liver injury. Using intravital imaging and flow cytometry we found impaired Kupffer cell bacterial clearance and systemic bacterial dissemination in mice with liver injury. Increased PD-1 and PD-L1 expression was detected in Kupffer cells and lymphocyte subsets, respectively, during resolution of injury. Gene expression profiling of PD-1+ Kupffer cells revealed an immune-suppressive profile and reduced pathogen responses. Compared to wild-type, PD-1 deficient or anti-PD-1 treated mice with liver injury showed improved Kupffer cell bacterial clearance, reduced tissue bacterial load and protection from sepsis. Blood sample analyses of ALF patients revealed enhanced PD-1 and PD-L1 expression of monocytes and lymphocytes, respectively, and that plasma soluble PD-L1 levels predict patient outcome and sepsis. PD-1 in vitro blockade restored monocyte functionality. Our study describes a role for PD-1/PD-L1 axis in suppressing Kupffer cell and monocyte antimicrobial responses after liver injury and suggests anti-PD-1 immunotherapy as a strategy to reduce infection susceptibility in ALF.
Pinheiro D, Mawhin M-A, Prendecki M, et al., 2020, In-silico analysis of myeloid cells across the animal kingdom reveals neutrophil evolution by colony-stimulating factors, ELIFE, Vol: 9, ISSN: 2050-084X
Rahman MS, Haskard DO, Frost G, et al., 2020, Acute dietary saturated fat intake suppresses human monocyte subset inflammatory and chemokine responses, Publisher: OXFORD UNIV PRESS, Pages: 3622-3622, ISSN: 0195-668X
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.
Pinheiro D, Mahwin M-A, Prendecki M, et al., 2020, Analysis of receptor-ligand pairings and distribution of myeloid subpopulations across the animal kingdom reveals neutrophil evolution was facilitated by colony-stimulating factors
<jats:title>Abstract</jats:title><jats:p>Neutrophils or heterophils constitute the largest population of phagocytic granulocytes in the blood of mammals and birds. The development and function of neutrophils and monocytes is primarily governed by the granulocyte colony-stimulating factor receptor family (CSF3R/CSF3) and macrophage colony-stimulating factor receptor family (CSF1R/IL34/CSF1) respectively. Using various techniques this study considered how the emergence of receptor:ligand pairings shaped the distribution of blood myeloid cell populations. Comparative gene analysis supported the ancestral pairings of CSF1R/IL34 and CSF3R/CSF3, and the emergence of CSF1 later in tetrapod lineages after the advent of Jawed/Jawless fish. Further analysis suggested that the emergence of CSF3 lead to reorganisation of granulocyte distribution between amphibian and early reptiles. However, the advent of endothermy likely contributed to the dominance of the neutrophil/heterophil in modern-day mammals and birds. In summary, we show that the emergence of CSF3R/CSF3 was a key factor in the subsequent evolution of the modern-day mammalian neutrophil.</jats:p><jats:sec><jats:title>Impact statement</jats:title><jats:p>Colony-stimulating factors (CSFs) are important for myeloid phagocyte development. The emergence of CSF3/CSF3R in tetrapod lineages has uniquely contributed to physical, functional and structural adaptions observed in mammalian neutrophils.</jats:p></jats:sec>
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
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
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
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
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
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
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
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