title: Down-regulation of Stathmin Is Required for the Phenotypic Changes and Classical Activation of Macrophages.
abstract: Macrophages are important cells of innate immunity with specialized capacity for recognition and elimination of pathogens and presentation of antigens to lymphocytes for adaptive immunity. Macrophages become activated upon exposure to pro-inflammatory cytokines and pathogenic stimuli. Classical activation of macrophages with interferon-γ (IFNγ) and lipopolysaccharide (LPS) triggers a wide range of signaling events and morphological changes to induce the immune response. Our previous microtubule (MT) proteomic work revealed that the stathmin association with MTs is considerably reduced in activated macrophages, which contain significantly more stabilized MTs. Here, we show that there is a global decrease in stathmin levels, an MT catastrophe protein, in activated macrophages using both immunoblotting and immunofluorescent microscopy. This is an LPS-specific response that induces proteasome-mediated degradation of stathmin. We explored the functions of stathmin down-regulation in activated macrophages by generating a stable cell line overexpressing stathmin-GFP. We show that stathmin-GFP overexpression impacts MT stability, impairs cell spreading, and reduces activation-associated phenotypes. Furthermore, overexpressing stathmin reduces complement receptor 3-mediated phagocytosis and cellular activation, implicating a pivotal inhibitory role for stathmin in classically activated macrophages.
authors.affiliation: From the Departments of Cell and Systems Biology and Biological Sciences, University of Toronto Scarborough, Toronto, Ontario M1C 1A4, Canada.
authors.forename: Kewei
authors.initials: K
authors.lastname: Xu
authors.affiliation: From the Departments of Cell and Systems Biology and Biological Sciences, University of Toronto Scarborough, Toronto, Ontario M1C 1A4, Canada harrison@utsc.utoronto.ca.
authors.forename: Rene E
authors.initials: RE
authors.lastname: Harrison
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002460:Cell Line; D048430:Cell Shape / Q000276:immunology; D015536:Down-Regulation; D007371:Interferon-gamma / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D010587:Phagocytosis; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex; D055550:Protein Stability; D011951:Receptors, Complement / Q000378:metabolism; D034561:Sheep, Domestic; D050777:Stathmin / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D011951:Receptors, Complement; D050777:Stathmin; C493994:Stmn1 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D007371:Interferon-gamma; D016203:CDC2 Protein Kinase; D046988:Proteasome Endopeptidase Complex
keywords: activation; innate immunity; macrophage; microtubule; microtubule-associated protein; phagocytosis; stathmin