Metabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling

Handle URI:
http://hdl.handle.net/10754/552123
Title:
Metabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling
Authors:
Zeis, T.; Allaman, I.; Gentner, M.; Schroder, K.; Tschopp, J.; Magistretti, Pierre J. ( 0000-0002-6678-320X ) ; Schaeren-Wiemers, N.
Abstract:
Emerging as an important correlate of neurological dysfunction in Multiple Sclerosis (MS), extended focal and diffuse gray matter abnormalities have been found and linked to clinical manifestations such as seizures, fatigue and cognitive dysfunction. To investigate possible underlying mechanisms we analyzed the molecular alterations in histopathological normal appearing cortical gray matter (NAGM) in MS. By performing a differential gene expression analysis of NAGM of control and MS cases we identified reduced transcription of astrocyte specific genes involved in the astrocyte–neuron lactate shuttle (ANLS) and the glutamate–glutamine cycle (GGC). Additional quantitative immunohistochemical analysis demonstrating a CX43 loss in MS NAGM confirmed a crucial involvement of astrocytes and emphasizes their importance in MS pathogenesis. Concurrently, a Toll-like/IL-1β signaling expression signature was detected in MS NAGM, indicating that immune-related signaling might be responsible for the downregulation of ANLS and GGC gene expression in MS NAGM. Indeed, challenging astrocytes with immune stimuli such as IL-1β and LPS reduced their ANLS and GGC gene expression in vitro. The detected upregulation of IL1B in MS NAGM suggests inflammasome priming. For this reason, astrocyte cultures were treated with ATP and ATP/LPS as for inflammasome activation. This treatment led to a reduction of ANLS and GGC gene expression in a comparable manner. To investigate potential sources for ANLS and GGC downregulation in MS NAGM, we first performed an adjuvant-driven stimulation of the peripheral immune system in C57Bl/6 mice in vivo. This led to similar gene expression changes in spinal cord demonstrating that peripheral immune signals might be one source for astrocytic gene expression changes in the brain. IL1B upregulation in MS NAGM itself points to a possible endogenous signaling process leading to ANLS and GGC downregulation. This is supported by our findings that, among others, MS NAGM astrocytes express inflammasome components and that astrocytes are capable to release Il-1β in-vitro. Altogether, our data suggests that immune signaling of immune- and/or central nervous system origin drives alterations in astrocytic ANLS and GGC gene regulation in the MS NAGM. Such a mechanism might underlie cortical brain dysfunctions frequently encountered in MS patients.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division
Citation:
Metabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling 2015 Brain, Behavior, and Immunity
Publisher:
Elsevier BV
Journal:
Brain, Behavior, and Immunity
Issue Date:
Apr-2015
DOI:
10.1016/j.bbi.2015.04.013
Type:
Article
ISSN:
08891591
Additional Links:
http://linkinghub.elsevier.com/retrieve/pii/S0889159115001208
Appears in Collections:
Articles; Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorZeis, T.en
dc.contributor.authorAllaman, I.en
dc.contributor.authorGentner, M.en
dc.contributor.authorSchroder, K.en
dc.contributor.authorTschopp, J.en
dc.contributor.authorMagistretti, Pierre J.en
dc.contributor.authorSchaeren-Wiemers, N.en
dc.date.accessioned2015-05-03T13:46:11Zen
dc.date.available2015-05-03T13:46:11Zen
dc.date.issued2015-04en
dc.identifier.citationMetabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling 2015 Brain, Behavior, and Immunityen
dc.identifier.issn08891591en
dc.identifier.doi10.1016/j.bbi.2015.04.013en
dc.identifier.urihttp://hdl.handle.net/10754/552123en
dc.description.abstractEmerging as an important correlate of neurological dysfunction in Multiple Sclerosis (MS), extended focal and diffuse gray matter abnormalities have been found and linked to clinical manifestations such as seizures, fatigue and cognitive dysfunction. To investigate possible underlying mechanisms we analyzed the molecular alterations in histopathological normal appearing cortical gray matter (NAGM) in MS. By performing a differential gene expression analysis of NAGM of control and MS cases we identified reduced transcription of astrocyte specific genes involved in the astrocyte–neuron lactate shuttle (ANLS) and the glutamate–glutamine cycle (GGC). Additional quantitative immunohistochemical analysis demonstrating a CX43 loss in MS NAGM confirmed a crucial involvement of astrocytes and emphasizes their importance in MS pathogenesis. Concurrently, a Toll-like/IL-1β signaling expression signature was detected in MS NAGM, indicating that immune-related signaling might be responsible for the downregulation of ANLS and GGC gene expression in MS NAGM. Indeed, challenging astrocytes with immune stimuli such as IL-1β and LPS reduced their ANLS and GGC gene expression in vitro. The detected upregulation of IL1B in MS NAGM suggests inflammasome priming. For this reason, astrocyte cultures were treated with ATP and ATP/LPS as for inflammasome activation. This treatment led to a reduction of ANLS and GGC gene expression in a comparable manner. To investigate potential sources for ANLS and GGC downregulation in MS NAGM, we first performed an adjuvant-driven stimulation of the peripheral immune system in C57Bl/6 mice in vivo. This led to similar gene expression changes in spinal cord demonstrating that peripheral immune signals might be one source for astrocytic gene expression changes in the brain. IL1B upregulation in MS NAGM itself points to a possible endogenous signaling process leading to ANLS and GGC downregulation. This is supported by our findings that, among others, MS NAGM astrocytes express inflammasome components and that astrocytes are capable to release Il-1β in-vitro. Altogether, our data suggests that immune signaling of immune- and/or central nervous system origin drives alterations in astrocytic ANLS and GGC gene regulation in the MS NAGM. Such a mechanism might underlie cortical brain dysfunctions frequently encountered in MS patients.en
dc.publisherElsevier BVen
dc.relation.urlhttp://linkinghub.elsevier.com/retrieve/pii/S0889159115001208en
dc.rightsThis is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ).en
dc.subjectBrain energy homeostasisen
dc.subjectGray matter pathologyen
dc.subjectInflammasomesen
dc.subjectAstrocyte–neuron lactate shuttleen
dc.subjectMultiple Sclerosisen
dc.subjectNormal appearing gray matteren
dc.subjectCerebral cortexen
dc.titleMetabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signalingen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.identifier.journalBrain, Behavior, and Immunityen
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionNeurobiology, Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerlanden
dc.contributor.institutionLaboratory of Neuroenergetics and Cellular Dynamics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerlanden
dc.contributor.institutionDepartment of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerlanden
dc.contributor.institutionCentre de Neurosciences Psychiatriques, CHUV, Département de Psychiatrie, Site de Cery, CH-1008 Prilly/Lausanne, Switzerlanden
kaust.authorMagistretti, Pierre J.en
All Items in KAUST are protected by copyright, with all rights reserved, unless otherwise indicated.