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Cell. 2019 Jan 24;176(3):581-596.e18. doi: 10.1016/j.cell.2018.12.012. Epub 2019 Jan 17.

Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation.

Author information

1
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
2
Neuroimmunology Research Lab, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada.
3
Neuroimmunology Unit, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
4
Department of Epidemiology and Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA.
5
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: fquintana@bwh.harvard.edu.

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.

KEYWORDS:

IRE1α; Sigmar1; XBP1; astrocyte; glia; inflammation; multiple sclerosis; neurodegeneration; zebrafish

PMID:
30661753
PMCID:
PMC6440749
[Available on 2020-01-24]
DOI:
10.1016/j.cell.2018.12.012

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