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Astroglial‐derived lymphotoxin‐α exacerbates inflammation and demyelination, but not remyelination
Author(s) -
Plant Sheila R.,
Arnett Heather A.,
Ting Jenny Py.
Publication year - 2004
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.20089
Subject(s) - remyelination , multiple sclerosis , lymphotoxin , microglia , immunology , tumor necrosis factor alpha , inflammation , lymphotoxin alpha , demyelinating disease , medicine , gliosis , biology , central nervous system , neuroscience , myelin
Tumor necrosis factorα (TNFα) and lymphotoxin‐α (Ltα) are upregulated in and around multiple sclerosis plaques and are proposed to play a role during chronic inflammation in demyelinating disease. Despite the perceived detrimental role of these cytokines, human clinical trials inhibiting TNFα signaling has led to worsening of symptoms in multiple sclerosis (MS) patients. Our laboratory has verified a role for TNFα in the exacerbation of demyelination but, more importantly, has demonstrated a novel role for TNFα in reparative remyelination in a cuprizone‐induced demyelination model. This may explain the worsening of symptoms experienced by MS patients. In view of the cross‐talk in TNF family signaling, the aim of this study is to understand the role of Ltα in demyelination and remyelination in hopes of improving therapeutic strategies for MS. Using the same model, we show that mice lacking Ltα exhibit a delay in demyelination that is greater than that exhibited by TNFα null mice. In this model, Ltα is expressed primarily by astroglia. The delay in demyelination is accompanied by a delay in the loss of mature GSTπ‐positive oligodendrocytes in Ltα −/− mice compared with wild‐type mice. Ltα −/− mice have decreased numbers of microglia at the site of insult during demyelination, although the number of astrocytes present is similar between strains. In contrast to TNFα the lack of Ltα did not alter the time course of remyelination, or the number of mature oligodendrocytes during the remyelination phase. Since Ltα is detrimental in inflammation and demyelination, but not necessary for remyelination and repair, inhibiting Ltα signaling may represent a promising strategy to treat MS. © 2004 Wiley‐Liss, Inc.