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.

Brain-immune interactions in perinatal hypoxic-ischemic brain injury

“…Inflammatory actions of IL-1β are mediated by the type I IL-1 receptor (IL-1R). Recent evidence has shown that IL-1β decreases the proliferation and survival rates of neural precursor cells by activating IL-1β/IL-1R signaling and upregulating p53 and p53-mediated genes, which leads to cell cycle inhibition and Puma/Bax-mediated apoptosis in neural precursor cells (Guadagno et al , 2015). Moreover, increased IL-1β production by microglia and astrocytes is linked to upregulated expression of IL-1R on oligodendrocytes and increased apoptosis of oligodendrocytes in periventricular white matter of neonatal brain (Deng et al , 2014; Xie et al , 2016).…”

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

“…Neurons release several inflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 in response to infection by encephalitic flaviviruses, such as WNV and JEV [195]. As well as impairing BBB integrity [152], elevated levels of IL-1β can induce cell cycle arrest and apoptosis in neural precursor cells (NPCs) [196]. TNF-α impairs glutamate uptake by astrocytes, leading to neuronal death due to excitotoxicity [197].…”

Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways

“…Several studies indicate that IL-1β is antineurogenic (Koo and Duman, 2008;Ryan et al, 2013) by activation of the tumor suppressor p53 (Guadagno et al, 2015) or via adrenocortical activation (Goshen et al, 2008). Other findings suggest a proneurogenic effect of IL-1β (de la Mano et al, 2007;Xue et al, 2015).…”