Astrogliosis in EAE spinal cord: Derivation from radial glia, and relationships to oligodendroglia

Abstract

A prominent feature of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is the accumulation of enlarged, multipolar glial fibrillary acidic protein (GFAP) and brain lipid binding protein (BLBP) immunoreactive astroglia within and at the margins of the inflammatory demyelinative lesions. Whether this astrogliosis is due to both astroglial hyperplasia and hypertrophy or solely to astroglial hypertrophy is controversial. We now report that coincident with the first appearance of inflammation and clinical deficits in mice with myelin oligodendrocyte glycoprotein peptide (MOG peptide)-induced EAE, the radially oriented, bipolar, GFAP, and BLBP positive cells (adult radial glia) present in normal spinal cord white matter undergo mitosis and phenotypic transformation to hypertrophic astroglia. To facilitate visualization of relationships between these hypertrophic astroglia and dying and regenerating oligodendroglia, we used mice that express enhanced green fluorescent protein (EGFP) in cells of the oligodendroglial lineage. During the first week after onset of illness, markedly swollen EGFP+ cells without processes were seen within lesions, whereas EGFP+ cells that expressed immunoreactive cleaved caspase-3 were uncommon. These observations support the hypothesis that necrosis contributes to oligodendroglial loss early in the course of EAE. Later in the illness, EGFP+ cells accumulated amongst hypertrophic astroglia at the margins of the lesions, while the lesions themselves remained depleted of oligodendroglia, suggesting that migration of oligodendroglial lineage cells into the lesions was retarded by the intense perilesional gliosis.

Platelet-Activating Factor Production in the Spinal Cord of Experimental Allergic Encephalomyelitis Mice via the Group IVA Cytosolic Phospholipase A2-Lyso-PAFAT Axis

“…A number of inflammatory cells, such as T cells and macrophages, infiltrate the CNS through the broken blood-brain barrier in EAE mice. Furthermore, microglia and astrocytes are activated by cytokines produced by the infiltrating cells (40,41). The expression and activity of LysoPAFAT were significantly elevated in SCs of EAE mice as compared with those of naive mice (Figs.…”

Fatal Neurological Disease in Scrapie-Infected Mice Induced for Experimental Autoimmune Encephalomyelitis

“…Astrocytosis is also a feature of CNS inflammation, as is the case for EAE (2,33). Figure 4, panel II, shows massive immunostaining for GFAP in coinduced mouse brain stems (medulla oblongata) compared to the moderate GFAP immunostaining in both EAE-and scrapie-induced controls.…”

Gp130-Dependent Astrocytic Survival Is Critical for the Control of Autoimmune Central Nervous System Inflammation

“…Interestingly, reactive astrocytes also restrict leukocyte infiltration, demyelination, tissue destruction, and motor deficits after traumatic spinal cord injury (43), which further argues for an immunosuppressive function of astrogliosis. However, astrogliosis may not always be protective, because reactive astrocytes inhibit axonal regeneration after spinal cord injury (44) and may prevent oligodendrocyte invasion into demyelinated areas in EAE (7).…”

“…This astrocytic NF-kB activation is critically regulated by IL-17-mediated activation of Act1; in the absence of astrocytic Act1 signaling, mice are largely protected from EAE and CD4 T cell infiltration to the spinal cord (4,5). At later stages of EAE, reduced uptake of toxic molecules, inhibition of remyelination by scar formation, and blocking of axonal regeneration may contribute to disease progression (6,7,reviewed in Ref. 8).…”