title: Regulation of microglial migration, phagocytosis, and neurite outgrowth by HO-1/CO signaling.
abstract: Clearance of infected and apoptotic neuronal corpses during inflammatory conditions is a fundamental process to create a favorable environment for neuronal recovery. Microglia are the resident immune cells and the predominant phagocytic cells of the CNS, showing a multitude of cellular responses upon activation. Here, we investigated in functional assays how the CO generating enzyme heme oxygenase 1 (HO-1) influences BV-2 microglial migration, clearance of debris, and neurite outgrowth of human NT2 neurons. Stimulation of HO-1 activity attenuated microglial migration in a scratch wound assay, and phagocytosis in a cell culture model of acute inflammation comprising lipopolysaccharide (LPS)-activated microglia and apoptosis-induced neurons. Application of a CO donor prevented the production of NO during LPS stimulation, and reduced microglial migration and engulfment of neuronal debris. LPS-activated microglia inhibited neurite elongation of human neurons without requiring direct cell-cell surface contact. The inhibition of neurite outgrowth was totally reversed by application of exogenous CO or increased internal CO production through supply of the substrate hemin to HO. Our results point towards a vital cytoprotective role of HO-1/CO signaling after microglial activation. In addition, they support a therapeutic potential of CO releasing chemical agents in the treatment of excessive inflammatory conditions in the CNS.
authors.affiliation: Division of Cell Biology, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Hannah
authors.initials: H
authors.lastname: Scheiblich
authors.affiliation: Division of Cell Biology, University of Veterinary Medicine Hannover, Hannover, Germany.|Center for Systems Neuroscience Hannover, Hannover, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Bicker
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002248:Carbon Monoxide / Q000378:metabolism*; D002448:Cell Adhesion; D049108:Cell Enlargement; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D051379:Mice; D017628:Microglia / Q000502:physiology*; D016501:Neurites / Q000502:physiology*; D015213:Neuroimmunomodulation / Q000502:physiology; D010587:Phagocytosis / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D002248:Carbon Monoxide; D051547:Heme Oxygenase-1
keywords: BV-2 microglia; NT2 model neurons; carbon monoxide; heme oxygenase; nitric oxide