The Role of p53 in the Regulation of Neuroinflammation

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DESCRIPTION (provided by applicant): Inflammation in the nervous system occurs during injury, stroke and several neurodegenerative diseases. Some degenerative diseases of the central nervous system (CNS) such as multiple sclerosis occur primarily due to abnormal inflammation. How inflammation impacts neurodegeneration is not completely understood but likely involves important roles for resident inflammatory cells known as microglia. Microglia exposed to infectious agents, injured CNS tissue, or abnormal protein accumulations (such as the beta-amyloid protein that accumulates in Alzheimer's disease), release inflammatory mediators that are often toxic to CNS cells and may produce a vicious cycle of chronic inflammation. Long term exposure to an inflammatory state can lead to the accumulation of reactive oxygen species (ROS) which may damage a variety of cellular components including DNA. This can lead to activation of cellular systems evolved to induce a cell suicide program called apoptosis. During experiments using an in vitro model of inflammation induced neuronal injury we observed that an important regulator of apoptosis, p53 is required in both neurons and microglia for inflammatory neurotoxicity. To determine how p53 is involved in the microglia response to a pro-inflammatory stimulus we examined global gene expression profiles from cultured microglia obtained from wild type and p53 deficient mice. The difference in gene expression between these two genotypes of microglia in conjunction with additional data on cytokine release from p53 deficient microglia led to the hypothesis that p53 participates in determining the activation phenotype in microglia cells in response to inflammatory signals. Microglia are cells in the macrophage linage, and several types of macrophage activation have been characterized. Two types of macrophage activation include "classical" tissue destructive activation and "alternative" activation in the down regulatory phase of the inflammatory response when macrophages participate in tissue repair. In this we will address the question of whether p53 acts during myeloid differentiation to influence to potential for polarized microglia activation or concurrently with the microglia response to a specific activation signal. We will also examine how p53 may interact with c-Maf, a transcription factor repressed by p53 in microglia, which has a previously described role in determining macrophage activation patterns. Finally, we will determine if p53 transits to microglia mitochondria in response to inflammatory stimuli, thereby impacting mitochondrial integrity and ROS generation. PUBLIC HEALTH RELEVANCE: Inflammation is a key pathological component of many common disease of the nervous system including Alzheimer's disease, Parkinson's disease and Stroke. Microglia are inflammatory cells that reside in the nervous system and we do not currently have a complete understanding of how these cells respond to injury or disease. The proposed experiments will enhance our understanding of how p53, a key regulator of cell division and survival may also be a fundamental determinate of how microglia respond to stimuli that initiate or perpetuate inflammation.