Abstract
Multiple sclerosis (MS) is characterized by episodes of inflammatory demyelination with progressive failure of remyelination. Prior studies using murine models of MS indicate that remyelination within the adult central nervous system (CNS) requires the expression and activity of TNFR2 and CXCR4 by oligodendrocyte progenitor cells (OPCs), promoting their proliferation and differentiation into mature oligodendrocytes. Here, we extend these studies by examining the role of TNFR2 in the expression of the CXCR4 ligand, CXCL12, within the corpus callosum (CC) during cuprizone (CPZ) intoxication and by demonstrating that lentiviral-mediated gene delivery of CXCL12 to the demyelinated CC improves OPC proliferation and myelin expression during remyelination. Activated astrocytes and microglia express both TNFR1 and TNFR2 within the demyelinated CC. However, CPZ intoxicated TNFR2−/− mice exhibit loss of up-regulation of CXCL12 in astrocytes with concomitant decreases in numbers of CXCR4+ NG2+ OPCs within the CC. While CXCR4 antagonism does not affect OPC migration from subventricular zones into the CC, it decreases their proliferation and differentiation within the CC. Stereotactic delivery of lentivirus expressing CXCL12 protein into the CC of acutely demyelinated TNFR2−/− mice increases OPC proliferation and expression of myelin. In contrast, chronically demyelinated wild-type mice, which exhibit significant loss of astrocytes and OPCs, are unable to be rescued via CXCL12 lentivirus alone but instead required engraftment of CXCL12-expressing astrocytes for increased myelin expression. Our results show that TNFR2 activation induces CXCL12 expression in the demyelinated CC via autocrine signaling specifically within astrocytes, which promotes OPC proliferation and differentiation. In addition, gene delivery of critical pro-myelinating proteins might be a feasible approach for the treatment of remyelination failure in MS.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-012-1034-0) contains supplementary material, which is available to authorized users.
Highlights
Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) that presents most often in a relapsing/remitting form, in which a period of demyelination is followed by a period of functional recovery [8, 56]
Astrocytes and microglia within the demyelinated corpus callosum (CC) of mice exposed to CPZ exhibited increased expression of TNF-a, and activation of TNFR2 proved essential for remyelination upon cessation of toxin
Quantitative confocal IHC detection of TNFR1 and TNFR2 in astrocytes (GFAP), microglia (IBA-1) and oligodendrocyte progenitor cells (OPCs) (PDGFRa) within the CC was performed on CNS tissues derived from 8-week-old naıve C57BL/6 mice (Supp Figure 1) and from those exposed to CPZ for 6 weeks (Fig. 1)
Summary
Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) that presents most often in a relapsing/remitting form, in which a period of demyelination is followed by a period of functional recovery [8, 56]. Studies examining the roles of TNF-a receptors in remyelination using a model of demyelination within the adult corpus callosum (CC) induced by the copper chelator cuprizone (CPZ), showed that TNFR2 activity is critical for the proliferation and differentiation of OPCs, resulting in attenuation of remyelination after cessation of CPZ [2]. These data suggest that TNFR2 plays a role in CNS repair of myelin and explain the failure of anti-TNF-a agents to alleviate disease in MS patients
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