Temporal characterization of neuroinflammation after cranial irradiation in the mouse Fredrik Kamme, Christine Cho, Curt Mazur, Holly Kordasiewicz, Eric Swayze Ionis Pharmaceuticals
Therapeutic cranial irradiation leads to chronic, progressive cognitive sequalae in pediatric patients. Animal data suggest that irradiation-induced persistent neuroinflammation underlies key deficits, including loss of neuronal progenitors in the hippocampus and impaired performance in novel object recognition testing1,2. Molecular analysis of microglia post irradiation in mice have shown elevations in phagocytic markers, type I IFN signaling and a similarity to aging3. We characterized the temporal evolution of neuroinflammation after cranial irradiation in mice with the goal to identify chronic processes that may underlie functional deficits in the model. Mice were irradiated at 10 Gy in orthovoltage and allowed to recover for 1, 2, 4 and 8 weeks. At each timepoint, microglia were isolated and analyzed by DGE sequencing. Microglial gene expression shows distinct inflammatory processes with different temporal profiles; a rapid onset but transient elevation in type I IFN response genes, a slow onset and progressive elevation in microglia priming genes and a rapid onset and chronic induction of p53-response genes. The neuroinflammatory response to cranial irradiation is multifaceted, suggesting there may be several signaling events underlying the gene expression changes. The temporal correlation of specific subsets of inflammatory responses with the chronic nature of functional deficits highlight these responses as potential targets for therapeutic intervention.
1. Michelle L. Monje, Hiroki Toda, & Theo D. Palmer. (2003). Inflammatory Blockade Restores Adult Hippocampal Neurogenesis, 302(December), 1760-1765. 2. Acharya, M. M., Green, K. N., Allen, B. D., Najafi, A. R., Syage, A., Minasyan, H., … Limoli, C. L. (2016). Elimination of microglia improves cognitive function following cranial irradiation. Scientific Reports, 6(April), 31545 3. Li, M. D., Burns, T. C., Kumar, S., Morgan, A. a., Sloan, S. a., & Palmer, T. D. (2015). Aging-like changes in the transcriptome of irradiated microglia. Glia, 63(5), 754-767.
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