Remyelination failure contributes to progressive neurodegeneration and accumulated clinical disability in multiple sclerosis (MS). The identification of critical pro-remyelinating signals would aide in the development of regenerative therapeutics to enhance remyelination in MS and potentially prevent disease progression. Macrophages are known to play a critical role in remyelination, ranging from debris clearance to promoting oligodendrocyte (OL) differentiation and therefore are an excellent target for pro- remyelinating therapy. But exactly how macrophages regulate OL differentiation/remyelination remains poorly understood. We performed bioinformatic analysis of a comprehensive and temporally resolved transcriptional profile of remyelination from the rat CNS, and identified an immunomodulatory enzyme called interleukin-4 induced gene 1 (IL4i1) in remyelinating lesions. The role of IL4i1 in CNS injury/repair has not previously been suggested. To investigate the role of IL4i1 in CNS remyelination, we will use gain- and loss-of-function strategies in mice by delivery of a recombinant IL4i1 into lesions, and by analysis of IL4i1 deficient mice, respectively Aim 1 will determine if IL4i1 positively regulates OL lineage progression and remyelination.
Aim 2 will determine if IL4i1 modulates inflammation during remyelination.
Remyelination failure in multiple sclerosis (MS) is a cause of neurodegeneration and accumulated clinical disability, therefore the identification of therapeutic targets for stimulating myelin repair in MS would help to restore myelin and protect axons from progressive degeneration. This project will investigate the role of an inflammation-associated factor in promoting remyelination. The results of this proposed study are expected to fill a gap in our knowledge on the immunomodulatory mechanism required for remyelination, which would impact on the research and development of pro-remyelination therapies in MS.
| Psachoulia, Konstantina; Chamberlain, Kelly A; Heo, Dongeun et al. (2016) IL4I1 augments CNS remyelination and axonal protection by modulating T cell driven inflammation. Brain 139:3121-3136 |
| Chamberlain, Kelly A; Nanescu, Sonia E; Psachoulia, Konstantina et al. (2016) Oligodendrocyte regeneration: Its significance in myelin replacement and neuroprotection in multiple sclerosis. Neuropharmacology 110:633-643 |
