A Neurodegeneration-Specific Gene-Expression Signature of Acutely Isolated Microglia from an Amyotrophic Lateral Sclerosis Mouse Model

• Published in: Cell reports (Cambridge) Vol. 4; no. 2; pp. 385 - 401
• Main Authors: Chiu, Isaac M., Morimoto, Emiko T.A., Goodarzi, Hani, Liao, Jennifer T., O’Keeffe, Sean, Phatnani, Hemali P., Muratet, Michael, Carroll, Michael C., Levy, Shawn, Tavazoie, Saeed, Myers, Richard M., Maniatis, Tom
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.07.2013; Elsevier
• Subjects: Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - immunology; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Disease Models, Animal; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia - immunology; Microglia - metabolism; Microglia - physiology; Transcriptome
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.06.018

Microglia are resident immune cells of the CNS that are activated by infection, neuronal injury, and inflammation. Here, we utilize flow cytometry and deep RNA sequencing of acutely isolated spinal cord microglia to define their activation in vivo. Analysis of resting microglia identified 29 genes that distinguish microglia from other CNS cells and peripheral macrophages/monocytes. We then analyzed molecular changes in microglia during neurodegenerative disease activation using the SOD1G93A mouse model of amyotrophic lateral sclerosis (ALS). We found that SOD1G93A microglia are not derived from infiltrating monocytes, and that both potentially neuroprotective and toxic factors, including Alzheimer’s disease genes, are concurrently upregulated. Mutant microglia differed from SOD1WT, lipopolysaccharide-activated microglia, and M1/M2 macrophages, defining an ALS-specific phenotype. Concurrent messenger RNA/fluorescence-activated cell sorting analysis revealed posttranscriptional regulation of microglia surface receptors and T cell-associated changes in the transcriptome. These results provide insights into microglia biology and establish a resource for future studies of neuroinflammation. [Display omitted] •Identification of specific marker genes for acutely isolated microglia•Progressive resident microglia transcriptome changes reveal in vivo activation phenotype•Microglial ALS disease activation signature distinct from M1/M2 macrophages•Parallel transcriptome and FACS analyses reveal T cell/microglia crosstalk Microglia are resident immune cells of the brain that are activated by infection or tissue damage. In this study, Maniatis and colleagues report the acute isolation, transcriptional profiling, and immunological analysis of microglia during disease activation in an ALS mouse model. A neurodegeneration-specific gene-expression signature is identified that includes induction of both neuroprotective and toxic factors and is distinct from that associated with M1/M2 macrophages. The data also provide a resource for future studies of microglia activation in neurodegenerative diseases.