CNTF is a major protective factor in demyelinating CNS disease: A neurotrophic cytokine as modulator in neuroinflammation

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). So far, immunological mechanisms responsible for demyelination have been the focus of interest. However, mechanisms regulating axon maintenance as well as glial precursor-cell proliferation and oligodendrocyte survival might also influence disease outcome. The cytokine ciliary neurotrophic factor (CNTF), which was originally identified as a survival factor for isolated neurons, promotes differentiation, maturation and survival of oligodendrocytes. To investigate the role of endogenous CNTF in inflammatory demyelinating disease, we studied myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in CNTF-deficient and wild-type C57BL/6 mice. Disease was more severe in CNTF-deficient mice and recovery was poor, with a 60% decrease in the number of proliferating oligodendrocyte precursor cells (OPCs) and a more than 50% increase in the rate of oligodendrocyte apoptosis. In addition, vacuolar dystrophy of myelin and axonal damage were more severe in CNTF-deficient mice. These specific pathological features could be prevented by treatment with an antiserum against tumor necrosis factor-alpha, suggesting that endogenous CNTF may counterbalance this effect of TNF-alpha (ref. 7). Here we identify a factor that modulates, in an inflammatory environment, glial cell survival and is an outcome determinant of EAE.

A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis

“…Slides were examined on an Olympus (Tokyo, Japan) Fluoview (FV300) confocal laser scanning microscope. An examiner who was unaware of the slide identity calculated the percent vacuolar change in the white matter of spinal cords, and quantitative analysis was performed as described previously (Linker et al, 2002). Cultured oligodendrocytes (OLs) derived from adult rat brains were stained with an O1 monoclonal antibody that recognizes galactocerebroside (GalC), a marker for mature OLs (Sommer and Schachner, 1981;Bansal et al, 1989).…”

Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system

“…H&E staining and immunohistochemistry were performed on 3 m cross paraffin or cryosections, as described in ref. 29, to determine inflammatory infiltrates, T cells (Serotec), macrophages, and DCs (BD). Omitting the primary antibody served as negative control.…”

Sox10 regulates ciliary neurotrophic factor gene expression in Schwann cells

“…Targeted inactivation of the Cntf gene in mice revealed its role in postnatal maintenance of motoneurons (17,18). Moreover, endogenous Cntf modulates onset and severity of disease in patients and mouse models for motoneuron disease and other neurological disorders (19)(20)(21). In progressive motor neuronopathy and wobbler mice, Cntf treatment protects motoneurons from cell death and improves motor performance (22,23), indicating that this factor is a major mediator of the protective effects of Schwann cells, both under physiological and pathological conditions.…”