title: Inflammation induces multinucleation of Microglia via PKC inhibition of cytokinesis, generating highly phagocytic multinucleated giant cells.
abstract: Microglia are brain macrophages, which can undergo multinucleation to give rise to multinucleated giant cells that accumulate with ageing and some brain pathologies. However, the origin, regulation and function of multinucleate microglia remain unclear. We found that inflammatory stimuli, including lipopolysaccharide, amyloid β, α-synuclein, tumour necrosis factor-α and interferon γ, but not interleukin-4, induced multinucleation of cultured microglia: primary rat cortical microglia and the murine microglial cell line BV-2. Inflammation-induced multinucleation was prevented by a protein kinase C (PKC) inhibitor Gö6976 (100 nM) and replicated by a PKC activator phorbol myristate acetate (160 nM). Multinucleation was reversible and not because of cell fusion or phagocytosis, but rather failure of cytokinesis. Time-lapse imaging revealed that some dividing cells failed to abscise, even after formation of long cytoplasmic bridges, followed by retraction of bridge and reversal of cleavage furrow to form multinucleate cells. Multinucleate microglia were larger and 2-4 fold more likely to phagocytose large beads and both dead and live PC12 cells. We conclude that multinucleate microglia are reversibly generated by inflammation via PKC inhibition of cytokinesis, and may have specialized functions/dysfunctions including the phagocytosis of other cells. Inflammation resulted in the accumulation of multiple nuclei per cell in cultured microglia. This multinucleation was reversible and due to a PKC-dependent block of the last step of cell division. Multinucleate microglia were larger and had a greater capacity to phagocytose other cells, suggesting they might remove neurons in the brain.
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: Tamara C
authors.initials: TC
authors.lastname: Hornik
authors.forename: Urte
authors.initials: U
authors.lastname: Neniskyte
authors.forename: Guy C
authors.initials: GC
authors.lastname: Brown
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D002459:Cell Fusion; D002460:Cell Line; D002467:Cell Nucleus / Q000473:pathology*; D048749:Cytokinesis / Q000502:physiology*; D005260:Female; D015726:Giant Cells / Q000502:physiology*; D007249:Inflammation / Q000473:pathology*; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D017628:Microglia / Q000473:pathology*; D016716:PC12 Cells; D010587:Phagocytosis / Q000502:physiology*; D061251:Primary Cell Culture; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051844:alpha-Synuclein / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D002227:Carbazoles; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D051844:alpha-Synuclein; C081021:Go 6976; D015847:Interleukin-4; D007371:Interferon-gamma; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate
keywords: Alzheimer's disease; HIV-associated dementia; abscission; microglia; neuroinflammation; phagocytosis