PUBLICATION
Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation
- Authors
- Wheeler, M.A., Jaronen, M., Covacu, R., Zandee, S.E.J., Scalisi, G., Rothhammer, V., Tjon, E.C., Chao, C.C., Kenison, J.E., Blain, M., Rao, V.T.S., Hewson, P., Barroso, A., Gutiérrez-Vázquez, C., Prat, A., Antel, J.P., Hauser, R., Quintana, F.J.
- ID
- ZDB-PUB-190122-1
- Date
- 2019
- Source
- Cell 176(3): 581-596.e18 (Journal)
- Registered Authors
- Keywords
- IRE1α, Sigmar1, XBP1, astrocyte, glia, inflammation, multiple sclerosis, neurodegeneration, zebrafish
- MeSH Terms
-
- Animals
- Astrocytes/metabolism*
- Central Nervous System/immunology
- Central Nervous System/metabolism*
- Computational Biology/methods
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Endoribonucleases/metabolism
- Environment
- Environmental Exposure/adverse effects
- Genome
- Genomics
- Humans
- Inflammation/metabolism
- Linuron/adverse effects
- Mice
- Mice, Inbred C57BL
- Multiple Sclerosis/immunology
- Protein Serine-Threonine Kinases/metabolism
- Receptors, sigma/drug effects
- Receptors, sigma/metabolism
- Signal Transduction
- X-Box Binding Protein 1/metabolism
- Zebrafish
- PubMed
- 30661753 Full text @ Cell
- CTD
- 30661753
Citation
Wheeler, M.A., Jaronen, M., Covacu, R., Zandee, S.E.J., Scalisi, G., Rothhammer, V., Tjon, E.C., Chao, C.C., Kenison, J.E., Blain, M., Rao, V.T.S., Hewson, P., Barroso, A., Gutiérrez-Vázquez, C., Prat, A., Antel, J.P., Hauser, R., Quintana, F.J. (2019) Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation. Cell. 176(3):581-596.e18.
Abstract
Genome-wide studies have identified genetic variants linked to neurologic diseases. Environmental factors also play important roles, but no methods are available for their comprehensive investigation. We developed an approach that combines genomic data, screens in a novel zebrafish model, computational modeling, perturbation studies, and multiple sclerosis (MS) patient samples to evaluate the effects of environmental exposure on CNS inflammation. We found that the herbicide linuron amplifies astrocyte pro-inflammatory activities by activating signaling via sigma receptor 1, inositol-requiring enzyme-1α (IRE1α), and X-box binding protein 1 (XBP1). Indeed, astrocyte-specific shRNA- and CRISPR/Cas9-driven gene inactivation combined with RNA-seq, ATAC-seq, ChIP-seq, and study of patient samples suggest that IRE1α-XBP1 signaling promotes CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, MS. In summary, these studies define environmental mechanisms that control astrocyte pathogenic activities and establish a multidisciplinary approach for the systematic investigation of the effects of environmental exposure in neurologic disorders.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping