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

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.

Th1 cells downregulate connexin 43 gap junctions in astrocytes via microglial activation

“…Although IL-1β and TNFα secreted from LPS-stimulated microglia have been reported to be the main factors that inhibit Cx43 expression and functions of GJs in astrocytes18, in our study, IL-1β alone decreased Cx43 protein levels and TNFα had no additional effect on the Cx43 protein reduction induced by IL-1β treatment. These data are in accordance with previous studies that reported IL-1β downregulates the expression of Cx43 in astrocyte-rich cultures2122. However, our present data differ from previous reports regarding the effects of proinflammatory cytokines on glial cells2324.…”

Metabolomic profiling of CSF in multiple sclerosis and neuromyelitis optica spectrum disorder by nuclear magnetic resonance

“…Interestingly, the expression level of GLUT1 (SLC2A1), a major glucose transporter in the BBB, is down-regulated in brain lesions of MS patients [46]. Moreover, a recent 1 H-NMR study reported reduced levels of serum glucose in MS [28].…”

Metabolic compartmentalization between astroglia and neurons in physiological and pathophysiological conditions of the neurovascular unit

“…However, a recent report has elucidated that oligodendroglia metabolize glucose glycolytically to produce lactate . Glucose supplied from microvessels can be used as a direct substrate for oligodendroglia to support neuronal energy metabolism . The CMR glc in the white matter is much less than that in the gray matter, and the exact contributions of astroglia, oligodendroglia, and neurons (axons) to CMR glc and the pathways of glucose transport to oligodendroglia and neurons remain to be solved.…”