Luisa Martinez-pomares
University of Nottingham, Life Sciences, Faculty Member
Macrophages are important orchestrators of inflammation during bacterial infection acting both as effector cells and as regulators of neutrophil recruitment and life span. Differently activated macrophage populations with distinct... more
Macrophages are important orchestrators of inflammation during bacterial infection acting both as effector cells and as regulators of neutrophil recruitment and life span. Differently activated macrophage populations with distinct inflammatory and microbicidal potential have been described. Our previous work unveiled a positive and a negative correlation between levels of IFN-γ and IL-17A, respectively, and lung function in cystic fibrosis, particularly in patients chronically infected with P. aeruginosa. This study sought to define key parameters in human anti-bacterial immunity under Th1- and Th17-dominated inflammatory conditions; the final aim was to identify unique characteristics that could be fine-tuned therapeutically to minimise tissue damage while maximising bacterial clearance. Towards this aim neutrophils were incorporated into cultures of macrophages treated with IFN-γ or IL-17A and infected with P. aeruginosa. The intent of this design was to model (i) initiation of in...
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Bacterial septicaemia is a major cause of mortality, but its pathogenesis remains poorly understood. In experimental pneumococcal murine intravenous infection, an initial reduction of bacteria in the blood is followed hours later by a... more
Bacterial septicaemia is a major cause of mortality, but its pathogenesis remains poorly understood. In experimental pneumococcal murine intravenous infection, an initial reduction of bacteria in the blood is followed hours later by a fatal septicaemia. These events represent a population bottleneck driven by efficient clearance of pneumococci by splenic macrophages and neutrophils, but as we show in this study, accompanied by occasional intracellular replication of bacteria that are taken up by a subset of CD169 splenic macrophages. In this model, proliferation of these sequestered bacteria provides a reservoir for dissemination of pneumococci into the bloodstream, as demonstrated by its prevention using an anti-CD169 monoclonal antibody treatment. Intracellular replication of pneumococci within CD169 splenic macrophages was also observed in an ex vivo porcine spleen, where the microanatomy is comparable with humans. We also showed that macrolides, which effectively penetrate macro...
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Patients with obstructive jaundice have an increased perioperative complication rate. Sepsis, bleeding, wound problems, renal and liver malfunction are all seen in these patients. Assessment of immune function has been an active research... more
Patients with obstructive jaundice have an increased perioperative complication rate. Sepsis, bleeding, wound problems, renal and liver malfunction are all seen in these patients. Assessment of immune function has been an active research area in these patients. This review will examine various aspects of immune functions in obstructive jaundice, discuss the recent research results and controversies and then go on to discuss the relevant mediators of immune function and some possible implications for treatment.
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Wild-type rabbitpox virus (RPV) produces red hemorrhagic pocks on the chorioallantoic membranes (CAMs) of embryonated chicken eggs. Like the crmA (SPI-2) gene of cowpox virus, disruption of the RPV ps/hr gene results in a mutant which... more
Wild-type rabbitpox virus (RPV) produces red hemorrhagic pocks on the chorioallantoic membranes (CAMs) of embryonated chicken eggs. Like the crmA (SPI-2) gene of cowpox virus, disruption of the RPV ps/hr gene results in a mutant which produces white pocks on the CAMs. An examination of the properties of the RPV(ps/hr) mutant in cell culture also reveals a significantly reduced host range, defined as the inability to form plaques, compared with wild-type virus. One of several cell types on which RPV(ps/hr) mutants fail to produce plaques is chicken embryo fibroblasts, cells which have been traditionally used to propagate spontaneously arising white pock mutants isolated from CAMs. The inability of the RPV(ps/hr) mutant to form plaques in chicken embryo fibroblasts correlates with a failure of a low multiplicity of infection to spread to neighboring cells and to form extracellular enveloped virus (EEV), although the formation and yields of infectious intracellular naked virus appear r...
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The use of chimaeric molecules bearing tags easily recognised by secondary reagents has facilitated the discovery of protein-protein and protein-carbohydrate interactions using binding assays in situ, in solution and in solid phase. In... more
The use of chimaeric molecules bearing tags easily recognised by secondary reagents has facilitated the discovery of protein-protein and protein-carbohydrate interactions using binding assays in situ, in solution and in solid phase. In this chapter we describe our experience in the use of proteins containing selected regions of the mannose receptor fused to the Fc region of human IgG1 or murine IgG2b. Using these reagents we have discovered new and unexpected ligands for the mannose receptor. These ligands were first detected in tissue section using standard histological techniques or ligand blots of whole tissue lysates, identified using affinity chromatography and N-terminal protein sequencing and confirmed using ligand blots or solid-phase-binding assays using purified proteins. These findings have dramatically changed the way we think about this molecule.
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We recently identified dectin-1 (betaGR) as a major beta-glucan receptor on leukocytes and demonstrated that it played a significant role in the non-opsonic recognition of soluble and particulate beta-glucans. Using a novel mAb (2A11)... more
We recently identified dectin-1 (betaGR) as a major beta-glucan receptor on leukocytes and demonstrated that it played a significant role in the non-opsonic recognition of soluble and particulate beta-glucans. Using a novel mAb (2A11) raised against betaGR, we show here that the receptor is not dendritic cell-restricted as first reported, but is broadly expressed, with highest surface expression on populations of myeloid cells (monocyte/macrophage (Mphi) and neutrophil lineages). Dendritic cells and a subpopulation of T cells also expressed the betaGR, but at lower levels. Alveolar Mphi, like inflammatory Mphi, exhibited the highest surface expression of betaGR, indicative of a role for this receptor in immune surveillance. In contrast, resident peritoneal Mphi expressed much lower levels of betaGR on the cell surface. Characterization of the nonopsonic recognition of zymosan by resident peritoneal Mphi suggested the existence of an additional beta-glucan-independent mechanism of zy...
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This unit includes protocols for the analysis of the targeting properties of Fc chimeric proteins and antibodies in mice in vivo. We present procedures to prepare the reagents to be tested under endotoxin-free conditions, suitable... more
This unit includes protocols for the analysis of the targeting properties of Fc chimeric proteins and antibodies in mice in vivo. We present procedures to prepare the reagents to be tested under endotoxin-free conditions, suitable injection sites, methodology for tissue collection, and processing, and labeling procedures to detect the injected material in situ.
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Research Interests: Immunology, Macrophages, Dendrimers, Nature, Dendritic Cells, and 14 moreInfluenza virus, Mice, Endocytosis, Animals, Antigen Presentation, Dendritic cell, influenza A virus, Lymph Node, Orthomyxoviridae Infections, Cell Adhesion Molecules, Humoral Immunity, Lymph nodes, mannose binding lectin, and Influenza vaccines
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Research Interests: Biological Chemistry, Western blotting, Biological Sciences, Spleen, Cell line, and 13 moreMice, Animals, Biological, Affinity chromatography, High Pressure Liquid Chromatography, CHEMICAL SCIENCES, Time Factors, Cysteine, Protein isoforms, Protein Binding, Sulfates, Mannose receptor, and Medical and Health Sciences
Mannose receptor (MR) is a C-type lectin primarily expressed by macrophages and dendritic cells. Its three distinct extracellular binding sites recognise a wide range of both endogenous and exogenous ligands, therefore MR has been... more
Mannose receptor (MR) is a C-type lectin primarily expressed by macrophages and dendritic cells. Its three distinct extracellular binding sites recognise a wide range of both endogenous and exogenous ligands, therefore MR has been implicated in both homeostatic processes and pathogen recognition. However, the function of MR in host defence is not yet clearly understood as MR-deficient animals do not display enhanced susceptibility to pathogens bearing MR ligands. This scenario is even more complex when considering the role of MR in innate immune activation as, even though no intracellular signalling motif has been identified at its cytoplasmic tail, MR has been shown to be essential for cytokine production, both pro-inflammatory and anti-inflammatory. Furthermore, MR might interact with other canonical pattern recognition receptors in order to mediate intracellular signalling. In this review, we have summarised recent observations relating to MR function in immune responses and focused on its participation in phagocytosis, antigen processing and presentation, cell migration and intracellular signalling.
Research Interests: Immune response, Pattern Recognition, Cell Migration, Cytokines, Macrophages, and 15 moreInnate immunity, Dendritic Cells, Signal Transduction, Biological Sciences, Humans, Immunity, Animals, Antigen Processing, Antigen Presentation, Dendritic cell, Immunobiology, Phagocytosis, Binding Site, Mannose receptor, and Medical and Health Sciences
Macrophage mannose receptor (MR) participates in pathogen recognition, clearance of endogenous serum glycoproteins, and antigen presentation. MR is also present on lymphatic vessels, where its function is unknown. Here we show that... more
Macrophage mannose receptor (MR) participates in pathogen recognition, clearance of endogenous serum glycoproteins, and antigen presentation. MR is also present on lymphatic vessels, where its function is unknown. Here we show that migration of lymphocytes from the skin into the draining lymph nodes through the afferent lymphatics is reduced in MR-deficient mice, while the structure of lymphatic vasculature remains normal in these animals. Moreover, in a tumor model the primary tumors grow significantly bigger in MR−/− mice than in the wild-type (WT) controls, whereas the regional lymph node metastases are markedly smaller. Adhesion of both normal lymphocytes and tumor cells to lymphatic vessels is significantly decreased in MR-deficient mice. The ability of macrophages to present tumor antigens is indistinguishable between the 2 genotypes. Thus, MR on lymphatic endothelial cells is involved in leukocyte trafficking and contributes to the metastatic behavior of cancer cells. Blockin...
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ADAMTS13 is a plasma metalloproteinase that regulates platelet adhesion and aggregation by cleaving ultra-large VWF multimers on the surfaces of endothelial cells. Autoantibodies directed against ADAMTS13 prohibit the processing of VWF... more
ADAMTS13 is a plasma metalloproteinase that regulates platelet adhesion and aggregation by cleaving ultra-large VWF multimers on the surfaces of endothelial cells. Autoantibodies directed against ADAMTS13 prohibit the processing of VWF multimers, initiating a rare and life-threatening disorder called acquired thrombotic thrombocytopenic purpura. The formation of autoantibodies depends on the activation of CD4+ T cells. This process requires immune recognition, endocytosis, and subsequent processing of ADAMTS13 into peptides that are presented on MHC class II molecules to CD4+ T cells by dendritic cells (DCs). In the present study, we investigated endocytosis of recombinant ADAMTS13 by immature monocyte-derived DCs using flow cytometry and confocal microscopy. After incubation of fluorescently labeled ADAMTS13 with DCs, significant uptake of ADAMTS13 was observed. Endocytosis of ADAMTS13 was completely blocked by the addition of EGTA and mannan. ADAMTS13 endocytosis was decreased in ...
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The in vitro binding of the macrophage mannose receptor to a range of different bacterial polysaccharides was investigated. The receptor was shown to bind to purified capsular polysaccharides from Streptococcus pneumoniae and to the... more
The in vitro binding of the macrophage mannose receptor to a range of different bacterial polysaccharides was investigated. The receptor was shown to bind to purified capsular polysaccharides from Streptococcus pneumoniae and to the lipopolysaccharides, but not capsular ...
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Research Interests: Immunohistochemistry, Macrophages, Dendritic Cells, In Situ Hybridization, Kidney, and 14 moreMice, Animals, Microglia, P-glycoprotein, Dendritic cell, Skin, Transfer Function, Phagocytosis, Endothelial cell, Experimental Medicine, Ligands, Lymphoid Tissue, Gene Expression Regulation, and Mannose receptor
Pseudomonas aeruginosa is an opportunistic pathogen that can cause severe infections at compromised epithelial surfaces, such those found in burns, wounds, and in lungs damaged by mechanical ventilation or recurrent infections,... more
Pseudomonas aeruginosa is an opportunistic pathogen that can cause severe infections at compromised epithelial surfaces, such those found in burns, wounds, and in lungs damaged by mechanical ventilation or recurrent infections, particularly in cystic fibrosis (CF) patients. CF patients have been proposed to have a Th2 and Th17-biased immune response suggesting that the lack of Th1 and/or over exuberant Th17 responses could contribute to the establishment of chronic P. aeruginosa infection and deterioration of lung function. Accordingly, we have observed that interferon (IFN)-γ production by peripheral blood mononuclear cells from CF patients positively correlated with lung function, particularly in patients chronically infected with P. aeruginosa. In contrast, IL-17A levels tended to correlate negatively with lung function with this trend becoming significant in patients chronically infected with P. aeruginosa. These results are in agreement with IFN-γ and IL-17A playing protective ...
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In this report we have reviewed our recent data which suggest a new function for MR in antigen delivery in lymphoid organs, together with highlighting three recent discoveries from our laboratory concerning the role of SR-A in adhesion,... more
In this report we have reviewed our recent data which suggest a new function for MR in antigen delivery in lymphoid organs, together with highlighting three recent discoveries from our laboratory concerning the role of SR-A in adhesion, phagocytosis of apoptotic cells and protection from endotoxic shock in mice. The diversity of functions mediated by each receptor demonstrates there is much yet to be discovered about how macrophages use their cell surface receptors to 'see' the external environment, and yet perform a wide range of strictly regulated functions.