title: Aging-like changes in the transcriptome of irradiated microglia.
abstract: Whole brain irradiation remains important in the management of brain tumors. Although necessary for improving survival outcomes, cranial irradiation also results in cognitive decline in long-term survivors. A chronic inflammatory state characterized by microglial activation has been implicated in radiation-induced brain injury. We here provide the first comprehensive transcriptional profile of irradiated microglia. Fluorescence-activated cell sorting was used to isolate CD11b+ microglia from the hippocampi of C57BL/6 and Balb/c mice 1 month after 10 Gy cranial irradiation. Affymetrix gene expression profiles were evaluated using linear modeling and rank product analyses. One month after irradiation, a conserved irradiation signature across strains was identified, comprising 448 and 85 differentially up- and downregulated genes, respectively. Gene set enrichment analysis demonstrated enrichment for inflammation, including M1 macrophage-associated genes, but also an unexpected enrichment for extracellular matrix and blood coagulation-related gene sets, in contrast previously described microglial states. Weighted gene coexpression network analysis confirmed these findings and further revealed alterations in mitochondrial function. The RNA-seq transcriptome of microglia 24-h postradiation proved similar to the 1-month transcriptome, but additionally featured alterations in apoptotic and lysosomal gene expression. Reanalysis of published aging mouse microglia transcriptome data demonstrated striking similarity to the 1-month irradiated microglia transcriptome, suggesting that shared mechanisms may underlie aging and chronic irradiation-induced cognitive decline. GLIA 2015;63:754-767.
authors.affiliation: Department of Neurosurgery, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Li
authors.forename: Terry C
authors.initials: TC
authors.lastname: Burns
authors.forename: Sunny
authors.initials: S
authors.lastname: Kumar
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Morgan
authors.forename: Steven A
authors.initials: SA
authors.lastname: Sloan
authors.forename: Theo D
authors.initials: TD
authors.lastname: Palmer
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000166:cytology* / Q000528:radiation effects; D039481:CD11b Antigen / Q000378:metabolism; D016764:Cell Polarity / Q000528:radiation effects; D016371:Cranial Irradiation; D005260:Female; D005434:Flow Cytometry; D053263:Gene Regulatory Networks / Q000528:radiation effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism* / Q000528:radiation effects*; D020411:Oligonucleotide Array Sequence Analysis; D013045:Species Specificity; D013997:Time Factors; D059467:Transcriptome / Q000528:radiation effects*
chemical_list: D039481:CD11b Antigen
keywords: aging; brain radiation; extracellular matrix; hippocampus; inflammation