The role of lymphotoxin alpha and lymphotoxin beta receptor in cuprizone induced demyelination and remyelination

Tumor necrosis factor alpha (TNFalpha) and lymphotoxin alpha (Ltalpha) are upregulated in and around multiple sclerosis (MS) plaques and are proposed to play a role during this inflammatory demyelinating disease. Despite the perceived detrimental role of these cytokines, clinical trials inhibiting TNFalpha signaling has lead to worsening of symptoms in MS patients. Our lab has demonstrated a novel role for TNFalpha in reparative remyelination using the Cuprzone-induced demyelination model which may explain the worsening of symptoms experienced by MS patients. Due to the crosstalk in TNF family signaling, the aim of this work was to understand the role of Ltalpha and LtbetaR in demyelination and remyelination in the hopes to improve therapeutic strategies for MS. Using the same model, we show that mice lacking Ltalpha or LtbetaR exhibit a delay in demyelination. In contrast to TNFalpha, the lack of either Ltalpha or LtbetaR did not significantly alter the time course of remyelination. However, LtbetaR-/- mice exhibited a high incidence of flagrant astrogliosis and neuronal atrophy leading to ventricular enlargement. Since both Ltalpha and LtbetaR are detrimental in inflammation and demyelination, but not necessary for remyelination and repair, inhibiting Ltalphabeta-LtbetaR signaling may represent a promising strategy to treat MS. However, this study also highlights the importance of LtbetaR to keep astrogliosis and neuronal pathology in check and strongly suggests that further research is warranted before pursuing treatment options for MS patients.; The remainder of this dissertation is devoted to the investigation of the stress-associated protein p8 which was found strongly upregulated during cuprizone-induced demyelination. By analyzing mice deficient in p8, we find that p8 is mildly detrimental during inflammation and demyelination. Moreover, we find that p8 is upregulated in the experimental autoimmune encephalomyelitis model of demyelination and in demyelinating plaques of human MS brain tissue. p8 has been shown to be a DNA-binding architectural protein with transcriptional regulatory properties. Thus, p8 and the genes it regulates may be useful therapeutic targets for the treatment of MS patients. The study of this gene in the future will be benefited by the availability of at least two different mouse models of MS.