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  • 1.
    Andersson, Kerstin
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Majeed, Meytham
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Fällman, Maria
    Department of Cell and Molecular Biology, University of Umeå, Umeå, Sweden.
    Yersinia pseudotuberculosis-induced calcium signaling in neutrophils is blocked by the virulence effector YopH1999In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 67, no 5, p. 2567-2574Article in journal (Refereed)
    Abstract [en]

    Pathogenic species of the genus Yersinia evade the bactericidal functions of phagocytes. This evasion is mediated through their virulence effectors, Yops, which act within target cells. In this study we investigated the effect of Yersinia pseudotuberculosis on Ca 2+ signaling in polymorphonuclear neutrophils. The intracellular free calcium concentration in single adherent human neutrophils was monitored during bacterial infection and, in parallel, the encounter between the bacteria and cells was observed. When a plasmid-cured strain was used for infection, adherence of a single bacterium to the cellular surface induced a β 1 integrin-dependent transient increase in the intracellular concentration of free calcium. This was, however, not seen with Yop-expressing wild-type bacteria, which adhered to the cell surface without generating any Ca 2+ signal. Importantly, the overall Ca 2+ homeostasis was not affected by the wild-type strain; the Ca 2+ signal mediated by the G-protein-coupled formyl-methionyl-leucyl- phenylalanine receptor was still functioning. Hence, the blocking effect was restricted to certain receptors and their signaling pathways. The use of different Yop mutant strains revealed that the protein tyrosine phosphatase YopH was responsible for the inhibition. This virulence determinant has previously been implicated in very rapid Yersinia-mediated effects on target cells as the key effector in the blockage of phagocytic uptake. The present finding, that Y. pseudotuberculosis, via YopH, specifically inhibits a self- induced immediate-early Ca 2+ signal in neutrophils, offers more-detailed information concerning the effectiveness of this virulence effector and implies an effect on Ca 2+-dependent, downstream signals.

  • 2. Constantin, G
    et al.
    Majeed, Meytham
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Giagulli, C
    Piccio, L
    Kim, JY
    Butcher, EC
    Laudanna, C
    Chemokines trigger immediate beta2 integrin affinity and mobility changes: Differential regulation and roles in lymphocytes arrest under flow.2000In: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 13, p. 759-769Article in journal (Refereed)
  • 3.
    Jerström Skarman, Petra
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Majeed, Meytham
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Ernst, Joel D.
    Department of Medicine, Division of Infectious Diseases, and The Rosalind Russell Arthritis Research Laboratory, University of California, San Francisco, USA.
    Carpentier, Jean-Louis
    Department of Morphology, University of Geneva, Switzerland.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Subcellular distribution of annexins, gelsolin and filamentous actin in adherent human neutrophils during phagocytosisManuscript (preprint) (Other academic)
    Abstract [en]

    Subcellular elevations of cytosolic free calcium concentration ([ea2+];), are critical for certain functional responses within the neutrophil, such asfilamentous actin (F-actin) reorganization and phagolysosome fusion (PLF). During this event, an accumulation of phospholipid- and calciumbinding proteins, annexins, can be seen in the periphagosomal area. A prerequisite for phagolysosome fusion is the elimination of F-actin around the phagosomes to facilitate the membrane contact between lysosomes and phagosomes. Gelsolin is a protein that severs F:actin by binding to the barbed ends, and thereby affect further polymerization. In this study, we used immunofluorescence staining and immunogold technique to analyse the distribution of annexin I, annexin III and gelsolin, in relation to the rearrangement ofF-actin during phagocytosos of complement-opsonized yeast particles by adherent human neutrophils. Iu unchallenged cells, both the aunexins and gelsolin were evenly distributed throughout the cells, whereas F-actin was found mostly in the protruding pseudopodia. Upon phagocytosis an accumulation of both. annexin I and annexin III, and gelsolin could be seen w1thm the vicimty of the phagocytic cups and phagosomes where they colocalized with Factin around the ingested particle.

    In calcium-depleted cells, the subcellular distributions of annexins and gelsolin were unaffected. On the other hand, there was a total increase inF-actin polymerization.

    Our data may indicate that gelsolin is important for the rearrangement of F-actin and that annexin I and annexin III, which are present in high concentrations in neutrophils, may participate in the following calciumdependent PLF in human neutrophils.

  • 4.
    Kälvegren, Hanna
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Majeed, Meytham
    Linköping University, Department of health and environment.
    Bengtsson, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Chlamydia pneumoniae binds to platelets and triggers P-selectin expression and aggregation: A causal role in cardiovascular disease?2003In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 23, no 9, p. 1677-1683Article in journal (Refereed)
    Abstract [en]

    Objective - Evidence linking Chlamydia pneumoniae to atherosclerotic cardiovascular disease is expanding. Platelets are considered to play an essential role in cardiovascular diseases, however, so far platelets have not been associated with an infectious cause of atherosclerosis. This study aims to clarify the interaction between Cpneumoniae and platelets and possibly present a novel mechanism in the pathogenesis of atherosclerosis.

    Methods and Results - The effects of C pneumoniae on platelet aggregation and secretion were assessed with lumiaggregometry, and the ability of C pneumoniae to bind to platelets and stimulate expression of P-selectin was analyzed with flow cytometry. We found that Cpneumoniae, at a chlamydia:platelet ratio of 1:15, adheres to platelets and triggers P-selectin expression after 1 minute and causes an extensive aggregation and ATP secretion after 20 minutes of incubation. Inhibition of glycoprotein IIb/IIIa with Arg-Gly-Asp-Ser or abciximab markedly reduced C pneumoniae-induced platelet aggregation. Exposure of C pneumoniae to polymyxin B, but not elevated temperature, abolished the stimulatory effects on platelet activation, suggesting that chlamydial lipopolysaccharide has an active role. In contrast, other tested bacteria had no or only moderate effects on platelet functions.

    Conclusion - Our findings demonstrate a new concept of how C pneumoniae activates platelets and thereby may cause atherosclerosis and thrombotic vascular occlusion.

     

  • 5.
    Lirvall, Margareta
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Majeed, Meytam
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Höddelius, Pia
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Wasteson, Åke
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Rosdahl, Inger
    Linköping University, Department of Biomedicine and Surgery, Dermatology. Linköping University, Faculty of Health Sciences.
    UVB radiation increases EGF receptor mobility and trafficking in human melanocytesManuscript (preprint) (Other academic)
    Abstract [en]

    For the human skin, UVB-radiation (290-320nm) is a very potent injurious agent. UV radiation is absorbed in the epidermis and reaching the melanocytes leads to proliferation via activation of growth factor reccptors. This may play a key role in the clonal expansion of melanocytes and be a critical step in carcinogenesis. We show that UVB-irradiated human epidermal melanocytes display an increased mobility of epidermal growth factor receptors (EGF-R) in the plane of the cell membrane, and that UVB affects the intracellular EGF-R transport to the nucleus. Using fluorescence photobleaching technique we show a time and dose dependent increase in the diffusion coefficient and mobile fraction of EGF-R. EGF-Rdiffuse with a low rate within the cell membrane in control cells, and the mobility increases 4-fold after single physiologic doses of UVB. Three-dimensional confocal microscopy reveals that EGF-R display a strilting difference in receptor distribution and intracellular transport before and after UVB irradiation. The EGF-Rclearly eo-localize with clathrin-coated pits within the cells. These results indicate that already single physiologic doses of UVB affect growth factor receptor mobility in cell membranes and intracellular trafficlting. This may be an important early step in the ultraviolet radiation-induced signal transduction pathway leading to cell proliferation.

  • 6.
    Majeed, Meytham
    Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Regulation of Attachment and Early Intracellular Development of Chlamydia trachomatis in Eucaryotic Cells1994Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The obligate intracellular bacterium, Chlamydia trachomatis , a common human pathogen, causing different diseases in both males and females, as well as in infants born to infected mothers. Occasionally, these diseases involve serious complications, such as blindness and infertility. C. trachomatis has a unique biphasic life cycle: after initial inclosure in membrane~bound endosomes, the infectious elementary bodies (EBs) reorganize to the metabolically actiVe forms (RBs); the RBs divide by binary fission, and after multiple divisions, they again differentiate to form new EBs, which are subsequently released from the host cell to start a new infectious cycle. As an attempt to investigate the early events of chlamydial infection, my results show that EBs bind with high affinity to collagen type I and heparan sulfate, suggesting that this selective affinity may mediate the attachment of chlamydiae to the surface of a host cell. ER-containing endosomes avoid fusion with host celllysosomes. However, within 30 min of form ation, these endosomes form one local aggregate in the central orperinuclear region of individual cells. This aggregation is reversible and time and temperature dependent, and requires viable EBs. Clathrin and F-actin are mobilized and colocalized with EB aggregates, suggesting that the aggregation of EBs is an active process that may be biologically involved in the infectivity of chlamydiae. The aggregation and inclusion formation of EBs, and the redistribution of F-actin seem to be controlled by both extra- and intracellular Ca2+, whereas the attachment and ingestion of EBs occur independently of Ca2+ in the growth medium and at low intracellular free Ca2+ [Ca2+]i. Moreover, chlamydiae do not induce any changes in the level of [Ca2+]i, this indicates that the aggregation of EBs requires a normal homeostasis of intracellular Ca2+. By affecting F-act:in reorganization and, putatively, certain Ca2+ -binding proteins, [Ca2+]i plays a vital role in the process of chlamydiae infection. The ca2+_ and phospholipid-binding proteins, annex.ins, are selectivelytranslocated during ehlamydial infection, i.e. annexins III, IV, and V, but not annexins I and VI, translocate to the proximity of chlamydial aggregates and inclusions. Annexins differ in their ability to associate with chlamydia-containing vesicles and inclusions. This fact implies that different factors regulate the interaction of annexins I and Ill with the membrane and also suggests that there is a selective regulatorymechanism that guides endosome aggregation and that is responsible for endosome avoiding lysosome fusion during chlamydial infection. Chlamydiae also induce mobilization of intracellular Ca2+ stores. This suggests that in a chlamydia-infected cell localized [Ca2+]i changes may occur by mobilization of Ca2+ stores at the sites of ca2+ action. The physiological role of ca2+ stores redistribution during infection of the host cells with chlamydiae might be to generate subceJlular [Ca2+]i gradients needed for the intracellular itinerary of the membrane trafficking of BE-containing endosomes.

  • 7.
    Majeed, Meytham
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Caveggion, E
    Lowell, CA
    Berton, G
    Role of Src kinases and Syk in Fc? receptor-mediated phagocytosis and phagosome-lysosome fusion2001In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 70, no 5, p. 801-811Article in journal (Refereed)
    Abstract [en]

    Phagocytosis is increased by Fc? receptors (Fc?Rs), and studies with syk-1- macrophages demonstrated that Syk kinase is required for Fc?TR phagocytosis. Similar studies with macrophages lacking the Src family kinases Hck, Fgr, and Lyn showed that these kinases are not required for phagocytosis but that they enhance the rate of particle engulfment. In this report we show that both wild-type and hck-1- fgr-1- macrophages expressed Fyn, Src, and Yes and that these kinases were activated on ingestion of immunoglobulin G (IgG)-coated particles and redistributed, together with Syk, to actin-rich phagocytic cups and the phagosomal membrane. At doses blocking IgG-dependent phagocytosis, the tyrosine kinase inhibitors PP1 and piceatannol inhibited both Src family kinase and Syk activities, as well as their redistribution to actin-rich phagocytic cups. Hck, Fgr, and Lyn were dispensable for lysosome-phagosome fusion (PLF) induced by IgG-coated particles. However, PP1 or piceatannol hampered unopsonized yeast-induced PLF despite the fact that they did not block yeast internalization.

  • 8.
    Majeed, Meytham
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Gustafsson, Mikael
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Kihlström, Erik
    Department of clinical microbiology, Örebro medical center hospital, Örebro, Sweden.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Roles of Ca2+ and F-actin in intracellular aggregation of Chlamydia trachomatis in eucaryotic cells1993In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 61, no 4, p. 1406-1414Article in journal (Refereed)
    Abstract [en]

    The effect of intracellular free Ca2+ ([Ca2+]i) on the intracellular aggregation of Chlamydia trachomatis serovars L2 and E in McCoy and HeLa cells is investigated. Loading the cells with the Ca2+ chelator MAPT/AM (1,2-bis-5-methyl-amino-phenoxylethane-N,N-n'-tetra-acetoxymethyl acetate), thereby decreasing the [Ca2+]i from 67 to 19 nM, decreased the number of cells with a local aggregation of chlamydiae in a dose-dependent manner. Neither the attachment nor the uptake of elementary bodies (EBs) was, however, affected after depletion of Ca2+ from the cells. There was no significant difference in the level of measured [Ca2+]i between infected and uninfected cells. Reducing the [Ca2+]i also significantly inhibited chlamydial inclusion formation. Differences in the organization of the actin filament network were observed in response to [Ca2+]i depletion. In Ca(2+)-depleted cells, where few EB aggregates were formed, few local accumulations of F-actin were observed in the cytosol. These results suggest that the aggregation of EBs in eucaryotic cells requires a normal homeostasis of intracellular Ca2+. By affecting F-actin reorganization and putatively certain Ca(2+)-binding proteins, [Ca2+]i plays a vital role in the infectious process of chlamydiae.

  • 9.
    Majeed, Meytham
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Krause, K-H
    Clark, RA
    Kihlström, Erik
    Linköping University, Faculty of Health Sciences. Linköping University, Department of health and environment. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Microbiology.
    Stendahl, Olle
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Localization of intracellular Ca2+ stores in HeLa cells during infection with Chlamydia trachomatis. 1999In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 112, p. 35-44Article in journal (Refereed)
  • 10.
    Majeed, Meytham
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Perskvist, Nasrin
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Ernst, Joel D.
    Division of Infectious Diseases and Rosalind Russell Research Laboratory, University of California, San Francisco and San Francisco General Hospital, San Francisco, CA, U.S.A..
    Orselius, Kristina
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Roles of calcium and annexins in phagocytosis and elimination of an attenuated strain of Mycobacterium tuberculosisin human neutrophils1998In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 24, no 5, p. 309-320Article in journal (Refereed)
    Abstract [en]

    The phagocytic function of neutrophils is a crucial element in the host defence against invading microorganisms. We investigated phagocytosis and intracellular killing of an attenuated strain of Mycobacterium tuberculosis(H37Ra) by human neutrophils focusing on the role of the cytosolic free calcium concentration [Ca2+]iand certain cytosolic calcium-dependent membrane-binding proteins annexins. Phagocytic uptake did not trigger a calcium rise and occurred independently of different calcium conditions, and in a serum-dependent manner. Changes in the viability of H37Ra were determined by agar plate colony count and a radiometric assay. Neutrophils showed a capacity to kill ingested mycobacteria and this occurred without a rise in [Ca2+]i. The ability to kill H37Ra decreased in the absence of extracellular calcium and when intra-extracellular calcium was reduced. Immunofluorescence staining revealed that during phagocytosis of H37Ra, annexins III, IV and VI translocated from cytoplasm to the proximity of the H37Ra-containing phagosomes, whereas the localization of annexin I and V remained unchanged. The translocation of annexin IV occurred even when Ca2+-depleted neutrophils ingested H37Ra in the absence of extracellular calcium. We concluded that neutrophil-mediated killing of mycobacteria is a Ca2+-dependent process. The fact that the association of certain annexins to the membrane vesicle containing H37Ra differ from other phagosomes suggests a selective regulatory mechanism during phagocytosis of mycobacteria by neutrophils.

  • 11. Nimeri, G
    et al.
    Majeed, Meytham
    Linköping University, Faculty of Arts and Sciences. Linköping University, Department of health and environment.
    Elwing, H
    Öhman, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Wetterö, Jonas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Rheumatology .
    Bengtsson, Torbjörn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Oxygen radical production in neutrophils interacting with platelets and surface-immobilized plasma proteins: role of tyrosine phosphorylation2003In: Journal of Biomedical Materials Research, ISSN 0021-9304, E-ISSN 1097-4636, Vol. 67A, no 2, p. 439-447Article in journal (Refereed)
    Abstract [en]

    The interaction between neutrophil granulocytes and platelets is considered to play an important role in the inflammatory process induced by an implanted foreign material. However, the cellular mechanisms involved remain incompletely understood. We used a luminol-dependent chemiluminescence (CL) technique to analyze the generation of reactive oxygen species (ROS) in human neutrophils interacting with different plasma protein-coated surfaces in the presence or absence of unstimulated or stimulated platelets. The role of tyrosine phosphorylation in the regulation of NADPH oxidase activity was evaluated with quantitative fluorescence microscopy and the specific tyrosine kinase inhibitor genistein. We found that the ROS-production is 2 to 3 times higher in neutrophils on immunoglobulin G (IgG)coated surfaces than in cells interacting with albumin- or fibrinogen-coated surfaces. Incubation with superoxide dismutase and catalase revealed that about 45% of the ROS was released extracellularly on IgG surfaces whereas corresponding values were 90% and 85% in neutrophils interacting with albumin and fibrinogen, respectively. The presence of platelets markedly increased the extracellular generation of ROS, mainly in neutrophils. interacting with IgG- or fibrinogen-coated surfaces whereas the intracellular production was only modestly affected. Quantitative fluorescence microscopy of neutrophils stained with FITC-conjugated anti-phosphotyrosine antibodies showed a correlation between tyrosine phosphorylation, cell spreading, and ROS production. Platelets markedly amplified the anti-phosphotyrosine staining on both fibrinogen- and IgG-coated surfaces whereas the low level of tyrosine phosphorylation in neutrophils on albumin-coated surfaces was not further elevated by platelets. Furthermore, the tyrosine kinase inhibitor genistein inhibited both extra- and intracellular ROS production in neutrophils regardless of the presence of platelets. We demonstrate that plasma protein coating and the presence of platelets are crucial for the inflammatory response of adhering neutrophils and that the oxidative response correlates with the extent of tyrosine phosphorylation of proteins in focal contacts. (C) 2003 Wiley Periodicals, Inc.

  • 12.
    Wilsson, Åsa
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Majeed, Meytham
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Calcium requirements for vitronectin-mediated phagocytosis of Staphylococcus aureus by human neutrophilsManuscript (preprint) (Other academic)
    Abstract [en]

    In this paper we have shown that the intracellular free calcium concentration ([Ca2+]i) in human neutrophils regulates phagocytosis of Staphylococcus aureus adherent to vitronectin-coated surfaces. When neutrophils were allowed to phagocytose bacteria bound to vitronectin- or albumin-coated surfaces in tbe presence of Ca2+, there were no obvious differences in the phagocytic activity. Ca2+-depleted neut:ropbils showed a reduced phagocytic activity on vitronectin-coated surfaces. However, the phagocytosis on albumin-coated surfaces was unaffected. Adding extracellularly Ca2+ restored the reduced phagocytic activity in Ca2+-depleted neutrophils on vitronectincoated surfaces. Similarly, using a GRGDSP-peptide to block tbe RGDmediated integrin attachment of tbe neutrophils to vitronectin restored tbe reduced phagocytic activity in Ca2+-depleted cells. Studying phagocytosis in non-migrating neutrophils adherent to vitronectin showed that ingestion of S. aureus occurred independently of Ca2+. This indicate that Ca2+ regulate the phagocytic activity of neutrophils on vitronectin-coated surfaces by regulating integrin-dependent cell directed motility.

  • 13.
    Wilsson, Åsa
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Majeed, Meytham
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Enhancement of chemoattractant-induced oxidative activation during phagocytosis of Staphylococcus aureus by human neutrophilsManuscript (preprint) (Other academic)
    Abstract [en]

    Several studies have shown that the production of oxygen radicals in human neutrophils can be influenced by prior exposure to different priming agents, but the mechanism underlying priming is not fully understood. The present study shows that under reduced Ca2+-conditions, phagocytosis of viable, but not heat-killed S. aureus can prepare Ca2+-depleted neutrophils for an increased oxidative activation when stimulated with fMLP in the presence of Ca2+. This enhancement of the produced oxygen radicals, induced by viable S. aureus, was not due to differences in phagocytic uptake between viable or heat-killed bacteria by the neutrophils. We could neither detect any difference in the upregulation of chemoattractant receptors such as the fMLP receptor or complement receptor 3 (CR3) to the neutrophil cell surface. Phagocytosis of viable S. aureus by Ca2+-depleted neutrophils under reduced Ca2+-conditions, induced tyrosine phosphorylation of two proteins identified as phospholipase Cγ2 (PLCγ2) and Syk. Pretreatment of neutrophils with U-73122 or piceatannol, to selectively inhibit PLC and Syk, respectively, resulted in a marked suppression of the oxidative response in primed neutrophils. In addition, PP1, a drug known to selectively inhibit Srcfamily protein kinases inhibited the oxidative response in primedneutrophils. Moreover, bacterial uptake activated the Src- family protein kinase Lyn, which was inhibited by PPl. Phagocytosis of viable or heatkilled S. aureus did not show any difference in activation of p38 mitogenactivated protein kinase (MAPK) and inhibition of this kinase by SB203580 did not suppress the fMLP-induced oxidative activation inprimed neutrophils. The findings demonstrate that both priming and the induction of tyrosine phosphorylation of PLCγ2, Syk and Lyn are Ca2+-independent events, thus indicating that the phosphorylation of these intracellular targets plays a central role during the neutrophil priming by S. aureus.

  • 14.
    Ydrenius, Liselotte
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Majeed, Meytham
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    J Rasmusson, Birgitta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Stendahl, Olle
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Särndahl, Eva
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Activation of cAMP-dependent protein kinase is necessary for actin rearrangements in human neutrophils during phagocytosis2000In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 67, no 4, p. 520-528Article in journal (Refereed)
    Abstract [en]

    We have investigated the role of cAMP and cAMP-dependent protein kinase (cAPK) in neutrophil phagocytosis. Inhibition of cAPK with H-89 reduced complement- and IgG-dependent phagocytosis to 83 and 46%, respectively. Fluorescence intensity measurements of phalloidin-stained actin in neutrophils showed a reduced amount of filamentous actin (F-actin) in pseudopods and around the phagosome in cells treated with H-89 or cAMP-elevating agents (forskolin and rolipram). The amount of phosphotyrosine-containing proteins was also reduced in pseudopods and around the phagosome. Taken together, the data show that cAMP/cAPK regulates F-actin reorganization during receptor-mediated phagocytosis, particularly triggered by IgG-FcR interaction. Our results support the hypothesis that active subcortical reorganization of F-actin is a prerequisite for FcR-mediated phagocytosis, but is less important during CR3-mediated ingestion.

  • 15.
    Zimmerli, Stefan
    et al.
    Division of Infectious Diseases and The Rosalind Russell Arthritis Research Laboratory, San Francisco General Hospital, University of California at San Francisco, San Francisco, California, USA.
    Majeed, Meytham
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Gustafsson, Mikael
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Sanan, David A.
    Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.
    Ernst, Joel D.
    Division of Infectious Diseases and The Rosalind Russell Arthritis Research Laboratory, San Francisco General Hospital, University of California at San Francisco, San Francisco, California, USA.
    Phagosome-Lysosome Fusion Is a Calcium-independent Event in Macrophages1996In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 132, no 1-2, p. 49-61Article in journal (Refereed)
    Abstract [en]

    Phagosome-lysosome membrane fusion is a highly regulated event that is essential for intracellular killing of microorganisms, Functionally, it represents a form of polarized regulated secretion, which is classically dependent on increases in intracellular ionized calcium ([Ca2+](i)). Indeed, increases in [Ca2+](i) are essential for phagosome-granule (lysosome) fusion in neutrophils and for lysosomal fusion events that mediate host cell invasion by Trypanosoma cruzi trypomastigotes, Since several intracellular pathogens survive in macrophage phagosomes that do not fuse with lysosomes, we examined the regulation of phagosome-lysosome fusion in macrophages. Macrophages (MO) were treated with 12.5 mu M bis-(2-amino-S-methylphenoxy) ethane-N,N,N',N',-tetraacetic acid tetraacetoxymethyl ester (MAPT/AM), a cell-permeant calcium chelator which reduced resting cytoplasmic [Ca2+]; from 80 nM to less than or equal to 20 nM and completely blocked increases in [Ca2+](i) in response to multiple stimuli, even in the presence of extracellular calcium, Subsequently, MO phagocytosed serum-opsonized zymosan, staphylococci, or Mycobacterium bovis, Microbes were enumerated by 4',6-diamidino-2-phenylindole, dihydrochloride (DAPI) staining, and phagosome-lysosome fusion was scored using both lysosome-associated membrane protein (LAMP-1) as a membrane marker and rhodamine dextran as a content marker for lysosomes, Confirmation of phagosomelysosome fusion by electron microscopy validated the fluorescence microscopy findings, We found that phagosome-lysosome fusion in MO occurs normally at very low [Ca2+](i) (less than or equal to 20 nM), Kinetic analysis showed that in MO none of the steps leading from particle binding to eventual phagosome-lysosome fusion are regulated by [Ca2+](i) in a rate-limiting way. Furthermore, confocal microscopy revealed no difference in the intensity of LAMP-1 immunofluorescence in phagolysosome membranes in calcium-buffered vs, control macrophages, We conclude that neither membrane recognition nor fusion events in the phagosomal pathway in macrophages are dependent on or regulated by calcium.

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