title: Astroglial-derived lymphotoxin-alpha exacerbates inflammation and demyelination, but not remyelination.
abstract: 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.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Sheila R
authors.initials: SR
authors.lastname: Plant
authors.forename: Heather A
authors.initials: HA
authors.lastname: Arnett
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism*; D002452:Cell Count; D003337:Corpus Callosum / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D005911:Gliosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000378:metabolism; D018836:Inflammation Mediators; D007527:Isoenzymes / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology; D009416:Nerve Regeneration / Q000235:genetics*; D009836:Oligodendroglia / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D018836:Inflammation Mediators; D007527:Isoenzymes; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha; D003471:Cuprizone; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C496557:Gstp1 protein, mouse