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

Zeis, T., Allaman, I., Gentner, M., Schroder, K., Tschopp, J., Magistretti, P. J. and Schaeren-Wiemers, N. (2015) Metabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling. Brain, Behavior, and Immunity, 48 313-325. doi:10.1016/j.bbi.2015.04.013


Author Zeis, T.
Allaman, I.
Gentner, M.
Schroder, K.
Tschopp, J.
Magistretti, P. J.
Schaeren-Wiemers, N.
Title Metabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling
Journal name Brain, Behavior, and Immunity   Check publisher's open access policy
ISSN 1090-2139
0889-1591
Publication date 2015-08
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.bbi.2015.04.013
Open Access Status DOI
Volume 48
Start page 313
End page 325
Total pages 13
Place of publication Maryland Heights, MO, United States
Publisher Academic Press [Elsevier]
Collection year 2016
Language eng
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.
Keyword Brain energy homeostasis
Gray matter pathology
Inflammasomes
Astrocyte-neuron lactate shuttle
Multiple Sclerosis
Normal appearing gray matter
Cerebral cortex
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Tue, 19 May 2015, 09:52:46 EST by Susan Allen on behalf of Institute for Molecular Bioscience