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

Environment
Genome
Multiple Sclerosis/immunology
Zebrafish
Protein Serine-Threonine Kinases/metabolism
Mice, Inbred C57BL
Signal Transduction
Humans
Inflammation/metabolism
Linuron/adverse effects
Genomics
Environmental Exposure/adverse effects
X-Box Binding Protein 1/metabolism
Animals
Endoribonucleases/metabolism
Computational Biology/methods
Receptors, sigma/drug effects
Receptors, sigma/metabolism
Astrocytes/metabolism*
Encephalomyelitis, Autoimmune, Experimental/immunology
Mice
Central Nervous System/immunology
Central Nervous System/metabolism*

(all 23)

PubMed

30661753 Full text @ Cell

CTD

30661753

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

Figures

Show all Figures

Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB	chemical treatment by environment: linuron, chemical treatment by environment: lipopolysaccharide, chemical treatment by environment: Cuprizon	Days 7-13	whole organism nos2a expression increased amount, abnormal	Fig. 1
AB	chemical treatment by environment: methyl carbamate, chemical treatment by environment: lipopolysaccharide, chemical treatment by environment: Cuprizon	Days 7-13	whole organism nos2a expression increased amount, abnormal	Fig. 1
AB	chemical treatment by environment: lipopolysaccharide, chemical treatment by environment: Cuprizon	Days 7-13	whole organism ccl20b expression increased amount, abnormal	Fig. 1
AB	chemical treatment by environment: lipopolysaccharide, chemical treatment by environment: Cuprizon	Days 7-13	whole organism il10 expression increased amount, abnormal	Fig. 1
AB	chemical treatment by environment: lipopolysaccharide, chemical treatment by environment: Cuprizon	Days 7-13	whole organism il17a/f1 expression increased amount, abnormal	Fig. 1
AB	chemical treatment by environment: lipopolysaccharide, chemical treatment by environment: Cuprizon	Days 7-13	whole organism il1b expression increased amount, abnormal	Fig. 1
AB	chemical treatment by environment: lipopolysaccharide, chemical treatment by environment: Cuprizon	Days 7-13	whole organism mpz expression decreased amount, abnormal	Fig. 1
AB	chemical treatment by environment: lipopolysaccharide, chemical treatment by environment: Cuprizon	Days 7-13	whole organism nos2a expression increased amount, abnormal	Fig. 1
mi2001Tg	chemical treatment by environment: lipopolysaccharide, chemical treatment by environment: Cuprizon	Days 7-13	radial glial cell nos2a expression increased amount, abnormal	Fig. 1

1 - 9 of 9

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
mi2001Tg	Tg(gfap:GFP)	Transgenic Insertion

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
encephalomyelitis			TAS
multiple sclerosis			TAS

Sequence Targeting Reagents

Fish

Fish
AB
mi2001Tg

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
GFP	EFG	GFP

Mapping

Wheeler et al., 2019 ZDB-PUB-190122-1 PMID:30661753

Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation

Wheeler et al., 2019

ZDB-PUB-190122-1
PMID:30661753