Failure to regenerate myelin in multiple sclerosis (MS) contributes to progressive axonal loss and accumulated disability. We have previously found that interleukin-four induced one (IL4i1), a macrophage-secreted immunoregulatory enzyme that serves to breakdown L-amino acids, modulates inflammation to promote remyelination in the mouse central nervous system (CNS). Moreover, we found that IL4i1 promotes remyelination by reducing pro-inflammatory CD4+ Th1 and Th17 cell activity in CNS lesions. Exactly how IL4i1 exerts its effect on the lesion microenvironment during remyelination remains unknown. However, the requirement for IL4i1 in remyelination suggests that a previously unknown mechanism involving amino acid metabolism operates in CNS lesions to control inflammation and promote repair. Here, we hypothesize that the regulation of amino acid metabolism in CNS lesions is critical for remyelination success. To this end, we will profile the levels of amino acids in CNS lesions over the course of remyelination by mass spectrometry analysis (Aim 1), determine if amino acid transport is required to regulate inflammation and remyelination (Aim 2), and determine if modulators of amino acid metabolism affects remyelination efficiency (Aim 3). The results of this study, if successful, will elucidate the role of amino acid metabolism on immune cells in CNS remyelination, and lead to future studies on modulators of amino acid metabolism as potential therapeutics for improving remyelination in MS.
Failure to regenerate myelin (remyelination), due in part to chronic inflammation in the central nervous system, results in progressive neurodegeneration and the accumulation of irreversible disability in multiple sclerosis (MS). This project will investigate if amino acid metabolism in central nervous system demyelinated lesions regulates inflammation to enable myelin repair in mice. The results of this study would improve our understanding of the immunoregulatory mechanisms governing remyelination, which would impact research and development of pharmacological therapies for improving remyelination in MS.