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Updated: Jun 1, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Transcription factor p53 influences microglial activation phenotype
Suman Jayadev1, Nicole K Nesser, Stephanie Hopkins
1Department of Neurology, University of Washington, Seattle, Washington 98195, USA.
Abstract:
Several neurodegenerative diseases are influenced by the innate immune response in the central nervous system (CNS). Microglia have proinflammatory 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 proinflammatory 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 proinflammatory phenotype, while p53 deficiency promotes phagocytosis and gene expression associated with alternative activation and anti-inflammatory functions.
Insights
The transcription factor p53 drives proinflammatory microglial activation in neurodegenerative diseases. Its absence promotes phagocytosis and anti-inflammatory functions, suggesting a therapeutic target for CNS disorders.
Area of Science:
- Neuroimmunology
- Neuroinflammation
- Molecular Neuroscience
Background:
- Innate immune responses in the central nervous system (CNS) influence neurodegenerative diseases.
- Microglia, the resident immune cells of the CNS, exhibit both pro-inflammatory and anti-inflammatory functions.
- Transcriptional regulation of microglial polarization remains poorly understood.
Purpose of the Study:
- To investigate the role of the transcription factor p53 in regulating microglial activation and function.
- To determine how p53 influences microglial responses to inflammatory stimuli.
- To explore the potential of targeting p53 for therapeutic interventions in neuroinflammatory conditions.
Main Methods:
- Utilized p53 knockout (p53(-/-)) and wild-type (p53(+/+)) mouse microglia.
- Stimulated microglia with interferon-γ (IFN-γ).
- Performed microarray analysis for global gene expression profiling.
- Assessed microglial phagocytic activity in vitro.
- Examined alternative activation markers (e.g., CD163) in vitro and in vivo.
Main Results:
- p53 deficiency blunted microglial response to IFN-γ, reducing pro-inflammatory gene expression and cytokine secretion.
- p53(-/-) microglia showed increased expression of genes linked to anti-inflammatory functions, phagocytosis, and tissue repair.
- p53(-/-) microglia exhibited enhanced phagocytic activity and markers of alternative macrophage activation.
- In HIV-associated neurocognitive disorders (HAND) brain tissue, p53 accumulation and CD163 expression marked distinct microglial subsets.
Conclusions:
- p53 promotes a pro-inflammatory microglial phenotype.
- Absence of p53 shifts microglia towards an alternative activation state, enhancing phagocytosis and anti-inflammatory functions.
- These findings highlight p53 as a key regulator of microglial polarization and a potential therapeutic target in neuroinflammation.
