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Microglia-derived IL-1β triggers p53-mediated cell cycle arrest and apoptosis in neural precursor cells
- Source :
- Cell Death & Disease
- Publication Year :
- 2015
- Publisher :
- Nature Publishing Group, 2015.
-
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.
- Subjects :
- Cyclin-Dependent Kinase Inhibitor p21
Lipopolysaccharides
Cancer Research
Cell cycle checkpoint
Neurogenesis
Immunology
Interleukin-1beta
Apoptosis
Cellular and Molecular Neuroscience
Interferon-gamma
Mice
Bcl-2-associated X protein
Neural Stem Cells
Precursor cell
Puma
Proto-Oncogene Proteins
medicine
Animals
Cells, Cultured
bcl-2-Associated X Protein
Mice, Knockout
biology
Microglia
Cell Biology
Cell Cycle Checkpoints
biology.organism_classification
Neural stem cell
Recombinant Proteins
Cell biology
Mitochondria
Nerve Regeneration
Enzyme Activation
Oxidative Stress
medicine.anatomical_structure
Proto-Oncogene Proteins c-bcl-2
biology.protein
Original Article
Tumor Suppressor Protein p53
Apoptosis Regulatory Proteins
Subjects
Details
- Language :
- English
- ISSN :
- 20414889
- Volume :
- 6
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Cell Death & Disease
- Accession number :
- edsair.doi.dedup.....20ace292eca646e8c191628c787b1bbf