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Dihydropyrimidinase-like 3 regulates the inflammatory response of activated microglia.

Abstract

Microglia, the resident immune cells of the CNS, are known to respond to injuries, infection and inflammation in the CNS by producing proinflammatory cytokines and phagocytosing cell debris and pathogens. In this study, we investigated the expression pattern and role of dihydropyrimidinase-like 3 (Dpysl3), a member of collapsin response mediator protein family, on the inflammatory reaction of microglia. Microarray analysis comparing the global gene expression profile of ameboid and ramified microglia has shown that Dpysl3 is mainly expressed in ameboid microglia in the 5-day postnatal rat brain. Immunohistochemical analysis revealed that Dpysl3 was intensely expressed in ameboid microglial cells in the rat brain till postnatal 7th day and then gradually diminished in ramified microglia of 2 weeks postnatal rat brain. Further, in vitro analysis confirmed that Dpysl3 expression was induced in activated BV-2 microglia treated with lipopolysaccharide (LPS). It is well documented that microglial activation by LPS increased the expression of inducible nitric oxide synthase (iNOS) and proinflammatory cytokines through the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity in BV-2 microglia. However, siRNA-mediated knockdown of Dpysl3 prevented the LPS-induced expression of iNOS and cytokines including interleukin-1 beta, and tumor necrosis factor-alpha as well as nuclear translocation of NF-κB in microglia. Remarkably, knockdown of Dpysl3 inhibited the migration of activated microglia coupled with deranged actin filament configuration (as revealed by F-actin cytoskeleton expression) in lamellipodia projecting from the cells. Knockdown of Dpysl3 also inhibited the phagocytic ability of activated microglia. These findings suggest that knockdown of Dpysl3 can inhibit activation, migration and phagocytic capability of microglia and consequently reduce neuroinflammation.

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  • Authors+Show Affiliations

    ,

    Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Blk MD10, 4 Medical Drive, Singapore 117597, Singapore.

    , ,

    Source

    Neuroscience 253: 2013 Dec 03 pg 40-54

    MeSH

    Age Factors
    Animals
    Animals, Newborn
    Brain
    Cell Line, Transformed
    Cell Movement
    Cell Survival
    Eliminative Behavior, Animal
    Gene Expression Regulation, Developmental
    Inflammation
    Interleukin-1beta
    Lipopolysaccharides
    Microglia
    Nerve Tissue Proteins
    Nitric Oxide Synthase Type II
    Phagocytes
    Rats
    Rats, Wistar
    Time Factors
    Tumor Necrosis Factor-alpha

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    23988434

    Citation

    Manivannan, J, et al. "Dihydropyrimidinase-like 3 Regulates the Inflammatory Response of Activated Microglia." Neuroscience, vol. 253, 2013, pp. 40-54.
    Manivannan J, Tay SS, Ling EA, et al. Dihydropyrimidinase-like 3 regulates the inflammatory response of activated microglia. Neuroscience. 2013;253:40-54.
    Manivannan, J., Tay, S. S., Ling, E. A., & Dheen, S. T. (2013). Dihydropyrimidinase-like 3 regulates the inflammatory response of activated microglia. Neuroscience, 253, pp. 40-54. doi:10.1016/j.neuroscience.2013.08.023.
    Manivannan J, et al. Dihydropyrimidinase-like 3 Regulates the Inflammatory Response of Activated Microglia. Neuroscience. 2013 Dec 3;253:40-54. PubMed PMID: 23988434.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Dihydropyrimidinase-like 3 regulates the inflammatory response of activated microglia. AU - Manivannan,J, AU - Tay,S S W, AU - Ling,E-A, AU - Dheen,S T, Y1 - 2013/08/27/ PY - 2013/04/27/received PY - 2013/08/14/revised PY - 2013/08/15/accepted PY - 2013/8/31/entrez PY - 2013/8/31/pubmed PY - 2014/6/20/medline KW - 4′,6-diamidino-2-phenylindol KW - AMC KW - CNS KW - CRMPs KW - DAPI KW - Dpysl3 KW - F-actin KW - IL-1β KW - LPS KW - NF-κB KW - NO KW - PBS KW - Phosphate-buffered saline KW - RMC KW - RT-PCR KW - Reverse Transcription–Polymerase Chain Reaction KW - TNF-α KW - ameboid microglial cells KW - central nervous system KW - collapsin response mediator proteins KW - dihydropyrimidinase like 3 KW - filamentous actin KW - iNOS KW - inducible nitric oxide synthase KW - interleukin-1 beta KW - lipopolysaccharide KW - microglia KW - migration KW - nitric oxide KW - nuclear factor kappa-light-chain-enhancer of activated B cells KW - phagocytosis KW - proinflammatory cytokines KW - ramified microglial cells KW - siRNA KW - small interfering RNA KW - tumor necrosis factor-alpha SP - 40 EP - 54 JF - Neuroscience JO - Neuroscience VL - 253 N2 - Microglia, the resident immune cells of the CNS, are known to respond to injuries, infection and inflammation in the CNS by producing proinflammatory cytokines and phagocytosing cell debris and pathogens. In this study, we investigated the expression pattern and role of dihydropyrimidinase-like 3 (Dpysl3), a member of collapsin response mediator protein family, on the inflammatory reaction of microglia. Microarray analysis comparing the global gene expression profile of ameboid and ramified microglia has shown that Dpysl3 is mainly expressed in ameboid microglia in the 5-day postnatal rat brain. Immunohistochemical analysis revealed that Dpysl3 was intensely expressed in ameboid microglial cells in the rat brain till postnatal 7th day and then gradually diminished in ramified microglia of 2 weeks postnatal rat brain. Further, in vitro analysis confirmed that Dpysl3 expression was induced in activated BV-2 microglia treated with lipopolysaccharide (LPS). It is well documented that microglial activation by LPS increased the expression of inducible nitric oxide synthase (iNOS) and proinflammatory cytokines through the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity in BV-2 microglia. However, siRNA-mediated knockdown of Dpysl3 prevented the LPS-induced expression of iNOS and cytokines including interleukin-1 beta, and tumor necrosis factor-alpha as well as nuclear translocation of NF-κB in microglia. Remarkably, knockdown of Dpysl3 inhibited the migration of activated microglia coupled with deranged actin filament configuration (as revealed by F-actin cytoskeleton expression) in lamellipodia projecting from the cells. Knockdown of Dpysl3 also inhibited the phagocytic ability of activated microglia. These findings suggest that knockdown of Dpysl3 can inhibit activation, migration and phagocytic capability of microglia and consequently reduce neuroinflammation. SN - 1873-7544 UR - https://www.unboundmedicine.com/medline/citation/23988434/Dihydropyrimidinase_like_3_regulates_the_inflammatory_response_of_activated_microglia_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(13)00711-2 DB - PRIME DP - Unbound Medicine ER -