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.
Highlights
IL-1β is synthesized in microglia as an inactive precursor protein that requires cleavage by caspase-1 to be transformed into its mature, biologically active form
It has been shown that hippocampal neurogenesis is impaired in mice chronically exposed to IL-1β in vivo and that IL-1β-induced inhibition of hippocampal progenitor cell proliferation was blocked by the IL-1R1 antagonist IL-1 receptor antagonist (IL-1RA).[22,23]
Microglia are the primary regulators of neuroinflammatory responses and previous studies have demonstrated that activated microglia release proinflammatory cytokines such as TNFα, IL-1β and IL-6 and decrease the proliferation and survival of neural precursor cells (NPCs).[13,17,18]
Summary
IL-1β is synthesized in microglia as an inactive precursor protein that requires cleavage by caspase-1 ( known as IL-1-converting enzyme or ICE) to be transformed into its mature, biologically active form. P53 is a sequencespecific transcription factor that can regulate the expression of genes involved in a number of cellular processes including cell cycle checkpoint control, metabolism, autophagy and apoptotic cell death.[25] the cyclin-dependent kinase inhibitor p21 is a p53 target gene known to have a key role in p53-mediated cell cycle arrest.[26,27] P53 has been shown to induce the expression of a number of genes involved in promoting apoptosis including Trp53INP1, Fas, Noxa and Puma (p53-upregulated modulator of apoptosis).[28] Recent evidence suggests that P53 has a role in regulating neurogenesis in the developing and adult brain.[29] p53 expression is enriched in NPCs during development and in adult neurogenic regions such as the subventricular zone and subgranular zone.[30,31] Postnatal p53-deficient mice exhibit increased proliferation within the SVZ and increased neurogenesis.[30] NPCs derived from p53-null mice exhibit reduced apoptosis and enhanced proliferation.[32] the potential role of p53 in regulating NPC proliferation and survival during neuroinflammatory conditions has not been investigated. We demonstrate that p53-deficient NPCs are resistant to apoptosis and proliferation defects induced by microgliaderived IL-1β, suggesting that p53 is a key regulator of NPC proliferation and survival during neuroinflammatory conditions
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