Evaluation of the PI3K/Akt/mTOR pathway in Multiple Sclerosis
Background The PI3K/AKT/mTOR pathway is an intracellular signaling pathway that regulates cell activation. proliferation, metabolism and apoptosis. Increasing body of data suggests that alterations in the PI3K/AKT/mTOR pathway may result in an enhanced susceptibility to autoimmunity. Aim of our work was to evaluate the involvement of the mTOR pathway in the pathogenesis of autoimmune diseases, with particular focus on Multiple Sclerosis (MS). Multiple sclerosis (MS) is one of the most common chronic inflammatory diseases of the central nervous system leading to demyelination and neurodegeneration. Drugs targeting the PI3K/AKT/mTOR pathway are currently under extensive investigation for their possible use as cancer chemotherapics and as immunosuppressive agents, but no clinical trial has been so far approved for the evaluation of their efficacy in the context of immunological disorders. Methods In the current study, we have firstly evaluated in silico the involvement of the mTOR network on the generation and progression of MS, making use of currently available whole-genome transcriptomic data. Also, the involvement of the mTOR network on oligondendrocyte function was studied, in order to ascertain whether treatment with drugs targeting the PI3K/Akt/mTOR pathway may be useful to promote the remyelination process, so to reverse disability in MS patients. Then, the data generated in silico were subjected to an ex-vivo evaluation. To this aims the involvement of mTOR was validated on a well-known animal model of MS and in vitro on Th17 cells. Results Our data indicate that there is a significant involvement of the mTOR network in the ethiopathogenesis of MS and that Rapamycin treatment may represent a useful therapeutic approach in the clinical setting. Ex vivo analysis showed that treatment of MOG-specific T cells from EAE affected mice with the mTOR inhibitor, Rapamycin, and the dual PI3K/mTOR inhibitor, BEZ-235, was able to significantly reduce antigen-specific proliferation. In addition, we show that Rapamycin treatment of murine T cell stimulated under Th17 conditions, was able to significantly inhibit the expression of some of the genes previously identified in the in silico analysis. On the other hand, our data showed that a significant involvement of the mTOR network could be observed only in the early phases of oligodendrocyte maturation, but not in the maturation process of adult oligodendrocytes and in the process of remyelination following demyelinating injury. Conclusions Overall, our study suggest that targeting the PI3K/mTOR pathway, although it may not be a useful therapeutic approach to promote remyelination in MS patients, it can be exploited to exert immunomodulation, preventing/delaying relapses, and to treat MS patients in order to slow down the progression of disability.
mTOR, autoimmunity, multiple sclerosis, rapamycin
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