Tumor necrosis factoralpha (
TNFalpha) and
lymphotoxin-alpha (Ltalpha) 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
TNFalpha signaling has led to worsening of symptoms in
multiple sclerosis (MS) patients. Our laboratory has verified a role for
TNFalpha in the exacerbation of
demyelination but, more importantly, has demonstrated a novel role for
TNFalpha 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 Ltalpha in
demyelination and remyelination in hopes of improving therapeutic strategies for MS. Using the same model, we show that mice lacking Ltalpha exhibit a delay in
demyelination that is greater than that exhibited by
TNFalpha null mice. In this model, Ltalpha is expressed primarily by astroglia. The delay in
demyelination is accompanied by a delay in the loss of mature GSTpi-positive oligodendrocytes in Ltalpha-/- mice compared with wild-type mice. Ltalpha-/- 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
TNFalpha the lack of Ltalpha did not alter the time course of remyelination, or the number of mature oligodendrocytes during the remyelination phase. Since Ltalpha is detrimental in
inflammation and
demyelination, but not necessary for remyelination and repair, inhibiting Ltalpha signaling may represent a promising strategy to treat MS.