Impact of Astrocyte Depletion upon Inflammation and Demyelination in a Murine Animal Model of Multiple Sclerosis

Abstract

Astrocytes play a key role in demyelinating diseases, like multiple sclerosis (MS), although many of their functions remain unknown. The aim of this study was to investigate the impact of astrocyte depletion upon de- and remyelination, inflammation, axonal damage, and virus distribution in Theiler`s murine encephalomyelitis (TME). Groups of two to six glial fibrillary acidic protein (GFAP)-thymidine-kinase transgenic SJL mice and SJL wildtype mice were infected with TME virus (TMEV) or mock (vehicle only). Astrocyte depletion was induced by the intraperitoneal administration of ganciclovir during the early and late phase of TME. The animals were clinically investigated while using a scoring system and a rotarod performance test. Necropsies were performed at 46 and 77 days post infection. Cervical and thoracic spinal cord segments were investigated using hematoxylin and eosin (H&E), luxol fast blue-cresyl violet (LFB), immunohistochemistry targeting Amigo2, aquaporin 4, CD3, CD34, GFAP, ionized calcium-binding adapter molecule 1 (Iba1), myelin basic protein (MBP), non-phosphorylated neurofilaments (np-NF), periaxin, S100A10, TMEV, and immunoelectron microscopy. The astrocyte depleted mice showed a deterioration of clinical signs, a downregulation and disorganization of aquaporin 4 in perivascular astrocytes accompanied by vascular leakage. Furthermore, astrocyte depleted mice showed reduced inflammation and lower numbers of TMEV positive cells in the spinal cord. The present study indicates that astrocyte depletion in virus triggered CNS diseases contributes to a deterioration of clinical signs that are mediated by a dysfunction of perivascular astrocytes.

Human Commensal Prevotella histicola Ameliorates Disease as Effectively as Interferon-Beta in the Experimental Autoimmune Encephalomyelitis

“…Similarly, reactive astrocytes are the main source of pro-inflammatory cytokine that plays a critical role in breaching the blood brain barrier (BBB) and induce recruitment of pathogenic immune cells into the CNS during MS and EAE (35)(36)(37). Astrocytes depletion is associated with reduced inflammation and demyelination in EAE mice (38). IFNb and/or P. histicola can modulate neuroinflammatory properties of microglia and astrocytes by reducing Th17 cells infiltration into the CNS, as a higher CNS infiltration of Th17 cells can augment their neuroinflammatory properties of microglia and astrocytes (26).…”

Delayed Onset Muscle Soreness (DOMS): The Repeated Bout Effect and Chemotherapy-Induced Axonopathy May Help Explain the Dying-Back Mechanism in Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases

“…PGE2 increases glutamate release from astrocytes, and glutamate excitotoxicity is implicated in ALS [ 79 ]. Astrocytes normally have a role in synapse formation, propagation of action potentials, maintenance of extracellular matrix homeostasis, and more important, maintenance of BSCB and BBB [ 87 ]. Furthermore, astrocytes are constantly engaged in intimate molecular crosstalk with microglial cells.…”

Connexins-Based Hemichannels/Channels and Their Relationship with Inflammation, Seizures and Epilepsy

“…Under neurodegenerative conditions, neuroinflammation involves the primordial participation of CNS cells, including microglia, oligodendrocytes, and astrocytes [62,63]. Astrocytes were first described by Dieters in 1865, and named by von Lenhossék in 1895, they are currently known as the most abundant cell type in the CNS [64,65].…”