The p53 Transcriptional Network Influences Microglia Behavior and Neuroinflammation

Abstract

The tumor-suppressor protein p53 belongs to a family of proteins that play pivotal roles in multiple cellular functions including cell proliferation, cell death, genome stability, and regulation of inflammation. Neuroinflammation is a common feature of central nervous system (CNS) pathology, and microglia are the specialized resident population of CNS myeloid cells that initiate innate immune responses. Microglia maintain CNS homeostasis through pathogen containment, phagocytosis of debris, and initiation of tissue-repair cascades. However, an unregulated pro-inflammatory response can lead to tissue injury and dysfunction in both acute and chronic inflammatory states. Therefore, regulation of the molecular signals that control the induction, magnitude, and resolution of inflammation are necessary for optimal CNS health. We and others have described a novel mechanism by which p53 transcriptional activity modulates microglia behaviors in vitro and in vivo. Activation of p53 induces expression of microRNAs (miRNAs) that support microglia pro-inflammatory functions and suppress anti-inflammatory and tissue repair behaviors. In this review, we introduce the previously described roles of the p53 signaling network and discuss novel functions of p53 in the microglia-mediated inflammatory response in CNS health and disease. Ultimately, improved understanding of the molecular regulators modulated by p53 transcriptional activity in microglia will enhance the development of rational therapeutic strategies to harness the homeostatic and tissue repair functions of microglia.

FIG. 1

p53-dependent miRNAs modulate key cellular functions. P53 regulates expression of several miRNAs with known roles in critical cellular functions. MiR-145 and miR-143 negatively regulate expression of the c-Myc transcription factor that modulates cell-cycle progression. P53 additionally orchestrates expression of miR-34 cluster miRNAs that target genes involved in apoptosis, cell-cycle arrest, including Bcl2 and cyclins. Additionally, p53 promotes expression of miRNAs that suppress tumor cell transformation and growth. These miRNAs, miR-192 and miR-215, downregulate expression of CDC7, MD2L1, and CUL5, genes involved in tumorgenesis.

FIG. 2

p53-dependent miRNAs modulate c-Maf in activated microglia. The p53-signaling network in microglia modulates c-Maf expression and promotes pro-inflammatory functions. p53 is activated in microglia by ROS, spontaneous DNA damage, or cellular stress associated with CNS disease and injury. p53-mediated transcriptional activity is required for the induction of p53-dependent miRNAs, miR-145, and miR-34a. These miRNAs target a transcriptional regulator, Twist2, for suppression, inhibiting the expression of the anti-inflammatory transcription factor c-Maf. In the absence of p53, microglia fail to induce expression of miR-155 in response to cytokine stimulation. MiR-155 also directly targets c-Maf mRNA for degradation.