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Search Results: 1 - 10 of 262054 matches for " Moira K. B. Whyte "
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The Identification of Markers of Macrophage Differentiation in PMA-Stimulated THP-1 Cells and Monocyte-Derived Macrophages
Marc Daigneault,Julie A. Preston,Helen M. Marriott,Moira K. B. Whyte,David H. Dockrell
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0008668
Abstract: Differentiated macrophages are the resident tissue phagocytes and sentinel cells of the innate immune response. The phenotype of mature tissue macrophages represents the composite of environmental and differentiation-dependent imprinting. Phorbol-12-myristate-13-acetate (PMA) and 1,25-dihydroxyvitamin D3 (VD3) are stimuli commonly used to induce macrophage differentiation in monocytic cell lines but the extent of differentiation in comparison to primary tissue macrophages is unclear. We have compared the phenotype of the promonocytic THP-1 cell line after various protocols of differentiation utilising VD3 and PMA in comparison to primary human monocytes or monocyte-derived macrophages (MDM). Both stimuli induced changes in cell morphology indicative of differentiation but neither showed differentiation comparable to MDM. In contrast, PMA treatment followed by 5 days resting in culture without PMA (PMAr) increased cytoplasmic to nuclear ratio, increased mitochondrial and lysosomal numbers and altered differentiation-dependent cell surface markers in a pattern similar to MDM. Moreover, PMAr cells showed relative resistance to apoptotic stimuli and maintained levels of the differentiation-dependent anti-apoptotic protein Mcl-1 similar to MDM. PMAr cells retained a high phagocytic capacity for latex beads, and expressed a cytokine profile that resembled MDM in response to TLR ligands, in particular with marked TLR2 responses. Moreover, both MDM and PMAr retained marked plasticity to stimulus-directed polarization. These findings suggest a modified PMA differentiation protocol can enhance macrophage differentiation of THP-1 cells and identify increased numbers of mitochondria and lysosomes, resistance to apoptosis and the potency of TLR2 responses as important discriminators of the level of macrophage differentiation for transformed cells.
A Method for the In Vivo Measurement of Zebrafish Tissue Neutrophil Lifespan
Giles Dixon,Philip M. Elks,Catherine A. Loynes,Moira K. B. Whyte
ISRN Hematology , 2012, DOI: 10.5402/2012/915868
Abstract:
Effective Caspase Inhibition Blocks Neutrophil Apoptosis and Reveals Mcl-1 as Both a Regulator and a Target of Neutrophil Caspase Activation
David J. Wardle,Joseph Burgon,Ian Sabroe,Colin D. Bingle,Moira K. B. Whyte,Stephen A. Renshaw
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015768
Abstract: Human tissue inflammation is terminated, at least in part, by the death of inflammatory neutrophils by apoptosis. The regulation of this process is therefore key to understanding and manipulating inflammation resolution. Previous data have suggested that the short-lived pro-survival Bcl-2 family protein, Mcl-1, is instrumental in determining neutrophil lifespan. However, Mcl-1 can be cleaved following caspase activity, and the possibility therefore remains that the observed fall in Mcl-1 levels is due to caspase activity downstream of caspase activation, rather than being a key event initiating apoptosis in human neutrophils.
Regulation of Neutrophil Senescence by MicroRNAs
Jon R. Ward,Paul R. Heath,James W. Catto,Moira K. B. Whyte,Marta Milo,Stephen A. Renshaw
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015810
Abstract: Neutrophils are rapidly recruited to sites of tissue injury or infection, where they protect against invading pathogens. Neutrophil functions are limited by a process of neutrophil senescence, which renders the cells unable to respond to chemoattractants, carry out respiratory burst, or degranulate. In parallel, aged neutrophils also undergo spontaneous apoptosis, which can be delayed by factors such as GMCSF. This is then followed by their subsequent removal by phagocytic cells such as macrophages, thereby preventing unwanted inflammation and tissue damage. Neutrophils translate mRNA to make new proteins that are important in maintaining functional longevity. We therefore hypothesised that neutrophil functions and lifespan might be regulated by microRNAs expressed within human neutrophils. Total RNA from highly purified neutrophils was prepared and subjected to microarray analysis using the Agilent human miRNA microarray V3. We found human neutrophils expressed a selected repertoire of 148 microRNAs and that 6 of these were significantly upregulated after a period of 4 hours in culture, at a time when the contribution of apoptosis is negligible. A list of predicted targets for these 6 microRNAs was generated from http://mirecords.biolead.org and compared to mRNA species downregulated over time, revealing 83 genes targeted by at least 2 out of the 6 regulated microRNAs. Pathway analysis of genes containing binding sites for these microRNAs identified the following pathways: chemokine and cytokine signalling, Ras pathway, and regulation of the actin cytoskeleton. Our data suggest that microRNAs may play a role in the regulation of neutrophil senescence and further suggest that manipulation of microRNAs might represent an area of future therapeutic interest for the treatment of inflammatory disease.
Drift-Diffusion Analysis of Neutrophil Migration during Inflammation Resolution in a Zebrafish Model
Geoffrey R. Holmes,Giles Dixon,Sean R. Anderson,Constantino Carlos Reyes-Aldasoro,Philip M. Elks,Stephen A. Billings,Moira K. B. Whyte,Visakan Kadirkamanathan,Stephen A. Renshaw
Advances in Hematology , 2012, DOI: 10.1155/2012/792163
Abstract: Neutrophils must be removed from inflammatory sites for inflammation to resolve. Recent work in zebrafish has shown neutrophils can migrate away from inflammatory sites, as well as die in situ. The signals regulating the process of reverse migration are of considerable interest, but remain unknown. We wished to study the behaviour of neutrophils during reverse migration, to see whether they moved away from inflamed sites in a directed fashion in the same way as they are recruited or whether the inherent random component of their migration was enough to account for this behaviour. Using neutrophil-driven photoconvertible Kaede protein in transgenic zebrafish larvae, we were able to specifically label neutrophils at an inflammatory site generated by tailfin transection. The locations of these neutrophils over time were observed and fitted using regression methods with two separate models: pure-diffusion and drift-diffusion equations. While a model hypothesis test (the F-test) suggested that the datapoints could be fitted by the drift-diffusion model, implying a fugetaxis process, dynamic simulation of the models suggested that migration of neutrophils away from a wound is better described by a zero-drift, “diffusion” process. This has implications for understanding the mechanisms of reverse migration and, by extension, neutrophil retention at inflammatory sites. 1. Introduction The fate of neutrophils following completion of the inflammatory programme is of critical importance for the outcome of episodes of acute inflammation and can determine whether there is prompt healing of a wound or the development of chronic inflammation and tissue injury. Neutrophils recruited to sites of inflammation may leave the site or die in situ [1]. The most widely accepted mechanism of neutrophil disposal is the programmed cell death or apoptosis, of the neutrophil followed by macrophage uptake and clearance (reviewed in [2]). Recently, other routes have been proposed; neutrophils may move away from the inflamed site into the bloodstream (“reverse transmigration” [3]), by migration through other tissues (“retrograde chemotaxis” or “reverse migration” [4–6]), or be lost into the inflammatory exudate [7, 8]. Current understanding of the process of reverse migration is reviewed elsewhere [9]. The uncertainty as to the in vivo fates of individual cells relates in part to the difficulty in following individual cells during inflammation resolution in vivo. The transgenic zebrafish model is emerging as a key model for the study of vertebrate immunity [10] and allows direct
A Cardinal Role for Cathepsin D in Co-Ordinating the Host-Mediated Apoptosis of Macrophages and Killing of Pneumococci
Martin A. Bewley,Helen M. Marriott,Calogero Tulone,Sheila E. Francis,Timothy J. Mitchell,Robert C. Read,Benny Chain,Guido Kroemer,Moira K. B. Whyte,David H. Dockrell
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1001262
Abstract: The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. Mice bearing a cathepsin D?/? hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function.
Staphylococcus aureus Induces Eosinophil Cell Death Mediated by α-hemolysin
Lynne R. Prince, Kirstie J. Graham, John Connolly, Sadia Anwar, Robert Ridley, Ian Sabroe, Simon J. Foster, Moira K. B. Whyte
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031506
Abstract: Staphylococcus aureus, a major human pathogen, exacerbates allergic disorders, including atopic dermatitis, nasal polyps and asthma, which are characterized by tissue eosinophilia. Eosinophils, via their destructive granule contents, can cause significant tissue damage, resulting in inflammation and further recruitment of inflammatory cells. We hypothesised that the relationship between S. aureus and eosinophils may contribute to disease pathology. We found that supernatants from S. aureus (SH1000 strain) cultures cause rapid and profound eosinophil necrosis, resulting in dramatic cell loss within 2 hours. This is in marked contrast to neutrophil granulocytes where no significant cell death was observed (at equivalent dilutions). Supernatants prepared from a strain deficient in the accessory gene regulator (agr) that produces reduced levels of many important virulence factors, including the abundantly produced α-hemolysin (Hla), failed to induce eosinophil death. The role of Hla in mediating eosinophil death was investigated using both an Hla deficient SH1000-modified strain, which did not induce eosinophil death, and purified Hla, which induced concentration-dependent eosinophil death via both apoptosis and necrosis. We conclude that S. aureus Hla induces aberrant eosinophil cell death in vitro and that this may increase tissue injury in allergic disease.
Monocytes Regulate the Mechanism of T-cell Death by Inducing Fas-Mediated Apoptosis during Bacterial Infection
Marc Daigneault,Thushan I. De Silva,Martin A. Bewley,Julie A. Preston,Helen M. Marriott,Andrea M. Mitchell,Timothy J. Mitchell,Robert C. Read,Moira K. B. Whyte,David H. Dockrell
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002814
Abstract: Monocytes and T-cells are critical to the host response to acute bacterial infection but monocytes are primarily viewed as amplifying the inflammatory signal. The mechanisms of cell death regulating T-cell numbers at sites of infection are incompletely characterized. T-cell death in cultures of peripheral blood mononuclear cells (PBMC) showed ‘classic’ features of apoptosis following exposure to pneumococci. Conversely, purified CD3+ T-cells cultured with pneumococci demonstrated necrosis with membrane permeabilization. The death of purified CD3+ T-cells was not inhibited by necrostatin, but required the bacterial toxin pneumolysin. Apoptosis of CD3+ T-cells in PBMC cultures required ‘classical’ CD14+ monocytes, which enhanced T-cell activation. CD3+ T-cell death was enhanced in HIV-seropositive individuals. Monocyte-mediated CD3+ T-cell apoptotic death was Fas-dependent both in vitro and in vivo. In the early stages of the T-cell dependent host response to pneumococci reduced Fas ligand mediated T-cell apoptosis was associated with decreased bacterial clearance in the lung and increased bacteremia. In summary monocytes converted pathogen-associated necrosis into Fas-dependent apoptosis and regulated levels of activated T-cells at sites of acute bacterial infection. These changes were associated with enhanced bacterial clearance in the lung and reduced levels of invasive pneumococcal disease.
Hypoxia. Hypoxia, hypoxia inducible factor and myeloid cell function
Sarah R Walmsley, Edwin R Chilvers, Moira KB Whyte
Arthritis Research & Therapy , 2009, DOI: 10.1186/ar2632
Abstract: Despite the evolution of respiratory and cardiovascular systems in multicellular higher organisms, the presence of physiological oxygen gradients within and across tissues is well described. At sites of tissue injury and inflammation, oxygen gradients become exaggerated – and it is within relatively oxygen-deplete tissue environments that myeloid cells are required to migrate and function. These sites are typified by empyemas, healing wounds and inflamed joints, where oxygen tensions in the range of 0 to 3 kPa are well documented [1]. It therefore makes sense that myeloid cells have adapted to function at these sites of relative tissue hypoxia, although subversion of this response may also be important in the persistent inflammation associated with inflammatory arthritides, notably rheumatoid arthritis where tissue hypoxia is also linked to disease severity and progression.Hypoxia inducible factor (HIF), a transcriptional regulator of cellular responses to oxygen deprivation, plays a crucial role in the regulating myeloid cell function in hypoxia and in inflammation more broadly. The roles of HIF in regulating key myeloid cell functions and signalling pathways are discussed in the present review and are summarized in Figure 1.The major pathway for sustainable production of ATP utilizes oxygen in the mitochondrial electron transport system, the process known as oxidative phosphorylation. Within the majority of cells there is a critical intracellular oxygen partial pressure required for respiration (the Pasteur point), below which cells produce ATP through the nonoxygen-requiring process of glycolysis, resulting in the accumulation of lactic acid. The relative importance of these aerobic and anaerobic pathways is highly dependent on the cell systems examined. Myeloid cells are unique in that they have adapted to operate by anaerobic metabolism, even when transiting oxygen-replete areas, with neutrophils incorporating 85% of their glucose uptake into lactate even under
The large scale geometry of some metabelian groups
J. Taback,K. Whyte
Mathematics , 2003,
Abstract: We study the large scale geometry of the upper triangular subgroup of PSL(2,Z[1/n]), which arises naturally in a geometric context. We prove a quasi-isometry classification theorem and show that these groups are quasi-isometrically rigid with infinite dimensional quasi-isometry group. We generalize our results to a larger class of groups which are metabelian and are higher dimensional analogues of the solvable Baumslag-Solitar groups BS(1,n).
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