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  1. Article ; Online: Azithromycin Augments Bacterial Uptake and Anti-Inflammatory Macrophage Polarization in Cystic Fibrosis.

    Tarique, Abdullah A / Tuladhar, Neeraj / Kelk, Dean / Begum, Nelufa / Lucas, Richard M / Luo, Lin / Stow, Jennifer L / Wainwright, Claire E / Bell, Scott C / Sly, Peter D / Fantino, Emmanuelle

    Cells

    2024  Volume 13, Issue 2

    Abstract: Background: Azithromycin (AZM) is widely being used for treating patients with cystic fibrosis (pwCF) following clinical trials demonstrating improved lung function and fewer incidents of pulmonary exacerba-tions. While the precise mechanisms remain ... ...

    Abstract Background: Azithromycin (AZM) is widely being used for treating patients with cystic fibrosis (pwCF) following clinical trials demonstrating improved lung function and fewer incidents of pulmonary exacerba-tions. While the precise mechanisms remain elusive, immunomodulatory actions are thought to be involved. We previously reported impaired phagocytosis and defective anti-inflammatory M2 macrophage polarization in CF. This study systematically analyzed the effect of AZM on the functions of unpolarized and M1/M2 polarized macrophages in CF.
    Methods: Monocytes, isolated from the venous blood of patients with CF (pwCF) and healthy controls (HCs), were differentiated into monocyte-derived macrophages (MDMs) and subsequently infected with
    Results: Following AZM treatment, both HC and CF MDMs exhibited a significant increase in
    Conclusions: This study highlights the cellular functions and molecular targets of AZM which may involve an improved uptake of both Gram-positive and Gram-negative bacteria, restored anti-inflammatory macrophage polarization in CF. This may in turn shape the reduced lung inflammation observed in clinical trials. In addition, we confirmed the role of ERK1/2 activation for bacterial uptake.
    MeSH term(s) Humans ; Azithromycin/pharmacology ; Gram-Negative Bacteria ; Anti-Bacterial Agents/pharmacology ; Cystic Fibrosis/drug therapy ; Escherichia coli ; Staphylococcus aureus ; Gram-Positive Bacteria ; Macrophages ; Anti-Inflammatory Agents/pharmacology
    Chemical Substances Azithromycin (83905-01-5) ; Anti-Bacterial Agents ; Anti-Inflammatory Agents
    Language English
    Publishing date 2024-01-16
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells13020166
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Live Fluorescence, Inverse Imaging of Cell Ruffling, and Macropinocytosis.

    Koh, Yvette W H / Hung, Yu / Tuladhar, Neeraj / Xiao, Zhijian / Brown, Darren L / Condon, Nicholas D / Stow, Jennifer L

    Journal of visualized experiments : JoVE

    2021  , Issue 174

    Abstract: Macropinocytosis is a highly conserved but still incompletely understood process that is essential for the uptake and ingestion of fluid, fluid-phase nutrients and other material in cells. The dramatic extension of cell surface ruffles, their closure to ... ...

    Abstract Macropinocytosis is a highly conserved but still incompletely understood process that is essential for the uptake and ingestion of fluid, fluid-phase nutrients and other material in cells. The dramatic extension of cell surface ruffles, their closure to form macropinosomes, and the maturation of internalized macropinosomes are key events in this pathway that can be difficult to capture using conventional confocal imaging based on tracking a bolus of fluorescent cargo. Fluorescent dextrans are commonly used experimentally as fluid phase markers for macropinosomes and for other endocytic pathways. A method the lab has adopted to optimize the imaging of dextran uptake involves using live imaging of cells bathed in high concentrations of fluorescent dextran in the medium, with the unlabeled cells appearing in relief (as black). The cell ruffles are highlighted to visualize ruffle closure, and internalized macropinosomes appear as fluorescent vacuoles in the cell interior. This method is optimal for visualizing macropinosome features and allows for easy segmentation and quantification. This paper describes dual-labeling of pathways with different sized dextrans and the co-expression of lipid probes and fluorescent membrane proteins to demark macropinosomes and other endosomes. The detection of internalized dextran at an ultrastructural level using correlative light and electron microscopy (CLEM) is also demonstrated. These cell processes can be imaged using multiple live imaging modalities, including in 3D. Taken together, these approaches optimize macropinosome imaging for many different settings and experimental systems.
    MeSH term(s) Cell Membrane ; Endosomes ; Microscopy, Electron ; Pinocytosis ; Vacuoles
    Language English
    Publishing date 2021-08-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Video-Audio Media
    ZDB-ID 2259946-0
    ISSN 1940-087X ; 1940-087X
    ISSN (online) 1940-087X
    ISSN 1940-087X
    DOI 10.3791/62870
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The transmembrane adapter SCIMP recruits tyrosine kinase Syk to phosphorylate Toll-like receptors to mediate selective inflammatory outputs.

    Liu, Liping / Lucas, Richard M / Nanson, Jeffrey D / Li, Yan / Whitfield, Jason / Curson, James E B / Tuladhar, Neeraj / Alexandrov, Kirill / Mobli, Mehdi / Sweet, Matthew J / Kobe, Bostjan / Stow, Jennifer L / Luo, Lin

    The Journal of biological chemistry

    2022  Volume 298, Issue 5, Page(s) 101857

    Abstract: Innate immune signaling by Toll-like receptors (TLRs) involves receptor phosphorylation, which helps to shape and drive key inflammatory outputs, yet our understanding of the kinases and mechanisms that mediate TLR phosphorylation is incomplete. Spleen ... ...

    Abstract Innate immune signaling by Toll-like receptors (TLRs) involves receptor phosphorylation, which helps to shape and drive key inflammatory outputs, yet our understanding of the kinases and mechanisms that mediate TLR phosphorylation is incomplete. Spleen tyrosine kinase (Syk) is a nonreceptor protein tyrosine kinase, which is known to relay adaptive and innate immune signaling, including from TLRs. However, TLRs do not contain the conserved dual immunoreceptor tyrosine-based activation motifs that typically recruit Syk to many other receptors. One possibility is that the Syk-TLR association is indirect, relying on an intermediary scaffolding protein. We previously identified a role for the palmitoylated transmembrane adapter protein SCIMP in scaffolding the Src tyrosine kinase Lyn, for TLR phosphorylation, but the role of SCIMP in mediating the interaction between Syk and TLRs has not yet been investigated. Here, we show that SCIMP recruits Syk in response to lipopolysaccharide-mediated TLR4 activation. We also show that Syk contributes to the phosphorylation of SCIMP and TLR4 to enhance their binding. Further evidence pinpoints two specific phosphorylation sites in SCIMP critical for its interaction with Syk-SH2 domains in the absence of immunoreceptor tyrosine-based activation motifs. Finally, using inhibitors and primary macrophages from SCIMP
    MeSH term(s) Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Macrophages/enzymology ; Membrane Proteins/metabolism ; Mice ; Mice, Knockout ; Phosphorylation ; Syk Kinase/metabolism ; Toll-Like Receptor 4/metabolism ; Toll-Like Receptors/genetics ; Toll-Like Receptors/metabolism ; Tyrosine/metabolism ; src-Family Kinases/metabolism
    Chemical Substances Adaptor Proteins, Signal Transducing ; Membrane Proteins ; Toll-Like Receptor 4 ; Toll-Like Receptors ; Tyrosine (42HK56048U) ; Syk Kinase (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2)
    Language English
    Publishing date 2022-03-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2022.101857
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uc I Zs.108: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: SCIMP is a spatiotemporal transmembrane scaffold for Erk1/2 to direct pro-inflammatory signaling in TLR-activated macrophages.

    Lucas, Richard M / Liu, Liping / Curson, James E B / Koh, Yvette W H / Tuladhar, Neeraj / Condon, Nicholas D / Das Gupta, Kaustav / Burgener, Sabrina S / Schroder, Kate / Ingley, Evan / Sweet, Matthew J / Stow, Jennifer L / Luo, Lin

    Cell reports

    2021  Volume 36, Issue 10, Page(s) 109662

    Abstract: Immune cells are armed with Toll-like receptors (TLRs) for sensing and responding to pathogens and other danger cues. The role of extracellular-signal-regulated kinases 1/2 (Erk1/2) in TLR signaling remains enigmatic, with both pro- and anti-inflammatory ...

    Abstract Immune cells are armed with Toll-like receptors (TLRs) for sensing and responding to pathogens and other danger cues. The role of extracellular-signal-regulated kinases 1/2 (Erk1/2) in TLR signaling remains enigmatic, with both pro- and anti-inflammatory functions described. We reveal here that the immune-specific transmembrane adaptor SCIMP is a direct scaffold for Erk1/2 in TLR pathways, with high-resolution, live-cell imaging revealing that SCIMP guides the spatial and temporal recruitment of Erk2 to membrane ruffles and macropinosomes for pro-inflammatory TLR4 signaling. SCIMP-deficient mice display defects in Erk1/2 recruitment to TLR4, c-Fos activation, and pro-inflammatory cytokine production, with these effects being phenocopied by Erk1/2 signaling inhibition. Our findings thus delineate a selective role for SCIMP as a key scaffold for the membrane recruitment of Erk1/2 kinase to initiate TLR-mediated pro-inflammatory responses in macrophages.
    MeSH term(s) Animals ; Cytokines/metabolism ; MAP Kinase Signaling System/physiology ; Macrophages/metabolism ; Mice, Transgenic ; Mitogen-Activated Protein Kinase 3/metabolism ; Phosphorylation ; Signal Transduction/physiology ; Toll-Like Receptor 4/metabolism ; Toll-Like Receptors/metabolism
    Chemical Substances Cytokines ; Toll-Like Receptor 4 ; Toll-Like Receptors ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24)
    Language English
    Publishing date 2021-12-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2021.109662
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: SCIMP is a universal Toll-like receptor adaptor in macrophages.

    Luo, Lin / Curson, James E B / Liu, Liping / Wall, Adam A / Tuladhar, Neeraj / Lucas, Richard M / Sweet, Matthew J / Stow, Jennifer L

    Journal of leukocyte biology

    2019  Volume 107, Issue 2, Page(s) 251–262

    Abstract: In innate immune cells, pathogens and danger signals activate TLRs, unleashing potent and tailored inflammatory responses. Previously, we reported that an immune-specific transmembrane adaptor, SLP adaptor and CSK interacting membrane protein (SCIMP), ... ...

    Abstract In innate immune cells, pathogens and danger signals activate TLRs, unleashing potent and tailored inflammatory responses. Previously, we reported that an immune-specific transmembrane adaptor, SLP adaptor and CSK interacting membrane protein (SCIMP), interacts with TLR4 via direct binding to its cytoplasmic TIR domain. SCIMP scaffolds a Src family kinase, Lyn, for TLR4 phosphorylation and activation. Consequently, SCIMP is able to direct selective production of the proinflammatory cytokines IL-6 and IL-12p40 downstream of TLR4 in macrophages. Here, we set out to investigate whether SCIMP also acts as an adaptor for other TLR family members. We report here that SCIMP is phosphorylated and activated in response to agonists of multiple TLRs, including TLR2, TLR3, TLR4, and TLR9. SCIMP also interacts with TLRs that are known to signal from both the cell surface and endosomal compartments. In so doing, this transmembrane adaptor presents Lyn, along with other effectors such as Grb2, Csk, and SLP65, to multiple TLRs during cellular activation. CRISPR-mediated knockout or silencing of SCIMP in macrophages alters TLR signaling outputs and the production of IL-6 and IL-12p40 downstream of multiple TLRs, and upon challenge with live bacteria. Furthermore, the selectivity in cytokine responses is preserved downstream of TLR3, with inducible expression of Il-12p40 and IL-6, but not IFNβ, being SCIMP dependent. SCIMP is thus a universal TLR adaptor for scaffolding the Lyn tyrosine kinase and its effectors to enable responses against a wide range of danger signals.
    MeSH term(s) Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Cells, Cultured ; Cytokines/metabolism ; Inflammation Mediators/metabolism ; Macrophages/cytology ; Macrophages/metabolism ; Mice ; Phosphorylation ; Signal Transduction ; Toll-Like Receptors/genetics ; Toll-Like Receptors/metabolism ; src-Family Kinases/genetics ; src-Family Kinases/metabolism
    Chemical Substances Adaptor Proteins, Signal Transducing ; Cytokines ; Inflammation Mediators ; Toll-Like Receptors ; lyn protein-tyrosine kinase (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2)
    Language English
    Publishing date 2019-08-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 605722-6
    ISSN 1938-3673 ; 0741-5400
    ISSN (online) 1938-3673
    ISSN 0741-5400
    DOI 10.1002/JLB.2MA0819-138RR
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 603: Show issues Location:
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