Investigating the Role of Amino Acid Metabolism in CNS Remyelination
Abstract
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the CNS, in which failure of remyelination corresponds with progressive neurodegeneration. Significant efforts have been made to identify critical molecular regulators and pharmacological compounds involved in promoting oligodendrocyte differentiation, therapeutic strategies targeting the obstacles of remyelination have been more challenging. In progressive forms of MS, increased proinflammatory microglia/macrophage density in chronic active and slowly expanding lesions is frequently observed and is associated with remyelination failure. Exactly how proinflammatory microglia/macrophages prevent remyelination, and whether therapeutic modulation of proinflammatory microglia/macrophage activity can improve remyelination remains unclear. We have made a novel preliminary observation that Slc7a5, a neutral amino acid (nAA) transporter, is upregulated in proinflammatory microglia/macrophages in mouse demyelinated lesions, and that pharmacological inhibition of Slc7a5, with the Slc7a5 selective inhibitor, JPH203, in mice after demyelination, significantly increased oligodendrocyte differentiation and reduced proinflammatory macrophage activation. Slc7a5 inhibition did not deplete microglia/macrophages in lesions, and instead, restored microglial homeostasis in lesions. We hypothesize that inhibition of nAA transport throughSlc7a5 reprograms pro-inflammatory cells in demyelinated lesions by returning them to a homeostatic state, leading to the secretion of pro-regenerative factors from homeostatic microglia that stimulate oligodendrocyte remyelination.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1192624
Entities
People
- Jeffrey K Huang
Organizations
- Georgetown University