title: Microglia-derived IL-1β triggers p53-mediated cell cycle arrest and apoptosis in neural precursor cells.
abstract: Neurogenesis persists in the adult brain and can contribute to learning and memory processes and potentially to regeneration and repair of the affected nervous system. Deregulated neurogenesis has been observed in neuropathological conditions including neurodegenerative diseases, trauma and stroke. However, the survival of neural precursor cells (NPCs) and newly born neurons is adversely affected by the inflammatory environment that arises as a result of microglial activation associated with injury or disease processes. In the present study, we have investigated the mechanisms by which microglia affect NPC proliferation and survival. Importantly, we demonstrate that interleukin-1β (IL-1β) produced by lipopolysaccharide/interferon-γ-activated microglia is necessary to induce cell cycle arrest and apoptosis in NPCs in vitro. Mechanistically, we show that IL-1β activates the tumor suppressor p53 through an oxidative stress-dependent mechanism resulting in p53-mediated induction of the cyclin-dependent kinase inhibitor p21 and the proapoptotic Bcl-2 (B-cell lymphoma-2) family members Puma (p53-upregulated modulator of apoptosis) and Noxa. Furthermore, we demonstrate that cell cycle arrest and apoptosis induced by recombinant IL-1β or activated microglia is attenuated in p53-deficient NPCs. Finally, we have determined that IL-1β induces NPC death via the p53-dependent induction of Puma leading to the activation of a Bax (Bcl-2-associated X protein)-mediated mitochondrial apoptotic pathway. In summary, we have elucidated a novel role for p53 in the regulation of NPC proliferation and survival during neuroinflammatory conditions that could be targeted to promote neurogenesis and repair in a number of neurological conditions.
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Guadagno
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Swan
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Shaikh
authors.affiliation: 1] Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada [2] Robarts Research Institute, University of Western Ontario, London, ON, Canada.
authors.forename: S P
authors.initials: SP
authors.lastname: Cregan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004789:Enzyme Activation; D007371:Interferon-gamma / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008070:Lipopolysaccharides; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology; D008928:Mitochondria / Q000378:metabolism; D009416:Nerve Regeneration / Q000502:physiology; D058953:Neural Stem Cells / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C508585:IL1B protein, human; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D007371:Interferon-gamma