Transcription factor p53 influences microglial activation phenotype

Abstract

Several neurodegenerative diseases are influenced by the innate immune response in the central nervous system (CNS). Microglia, have pro-inflammatory and subsequently neurotoxic actions as well as anti-inflammatory functions that promote recovery and repair. Very little is known about the transcriptional control of these specific microglial behaviors. We have previously shown that in HIV associated neurocognitive disorders (HAND), the transcription factor p53 accumulates in microglia and that microglial p53 expression is required for the in vitro neurotoxicity of the HIV coat glycoprotein gp120. These findings suggested a novel function for p53 in regulating microglial activation. Here we report that in the absence of p53, microglia demonstrate a blunted response to interferon-γ, failing to increase expression of genes associated with classical macrophage activation or secrete pro-inflammatory cytokines. Microarray analysis of global gene expression profiles revealed increased expression of genes associated with anti-inflammatory functions, phagocytosis and tissue repair in p53 knockout (p53−/−) microglia compared with those cultured from strain matched p53 expressing (p53+/+) mice. We further observed that p53−/− microglia demonstrate increased phagocytic activity in vitro and expression of markers for alternative macrophage activation both in vitro and in vivo. In HAND brain tissue, the alternative activation marker CD163 was expressed in a separate subset of microglia than those demonstrating p53 accumulation. These data suggest that p53 influences microglial behavior, supporting the adoption of a pro-inflammatory phenotype, while p53 deficiency promotes phagocytosis and gene expression associated with alternative activation and anti-inflammatory functions.

Moderate Dietary Restriction Reduces p53-Mediated Neurovascular Damage and Microglia Activation After Hypoxic Ischemia in Neonatal Brain

“…9 Upregulation of proinflammatory genes induced by interferon gamma was suppressed in p53 Ϫ/Ϫ microglia. 21 These findings indicated that p53 is also involved in endothelial cell injury and microglia activation after brain damage. We found that HI-induced upregulation of p53, BBB damage and microglia activation were attenuated by moderate DR. Inhibiting p53 decreased BBB damage and microglia activation in NL-HI pups, Figure 6.…”

Transcriptional control of microglia phenotypes in health and disease

“…The expression and activity of p53 increases in microglia in response to cellular stress, DNA damage, and oxidative stress (78)(79)(80). In postmortem brain tissues from patients with HIV-associated dementia (HAD) elevated levels of p53 were particularly prominent in the microglia (78,81). HIV-infected p53-deficient neuron/microglia cocultures showed increased neuronal survival compared with WT (78).…”

Emerging roles of p53 in glial cell function in health and disease

“…Exposing neural cultures to HIV-gp120 coat protein induces robust p53 activation and co-culture studies of cells from p53 knockout mice demonstrate that both neurons and microglia must express p53 for gp120-induced neurotoxicity (Garden et al, 2004). While p53 activity in neurons may promote activation of apoptotic cascades, the role of p53 in microglia appears more nuanced, promoting proinflammatory behaviors and suppressing microglia functions that might provide neurotrophic effects (Jayadev et al, 2011; Mukerjee et al, 2010). Exposing cultured astrocytes to Vpr leads to p53 activation and induction of downstream apoptotic pathways mediated by caspase-6 (Noorbakhsh et al, 2010).…”