Proteomic and lipidomic profiling of demyelinating lesions identifies fatty acids as modulators in lesion recovery

ABSTRACT: Summary After demyelinating injury of the central nervous system, resolution of the mounting acute inflammation is crucial for the initiation of a regenerative response. Here, we aim to identify fatty acids and lipid mediators that govern the balance of inflammatory reactions within demyelinating lesions. Using lipidomics, we identify bioactive lipids in the resolution phase of inflammation with markedly elevated levels of n-3 polyunsaturated fatty acids. Using fat-1 transgenic mice, which convert n-6 fatty acids to n-3 fatty acids, we find that reduction of the n-6/n-3 ratio decreases the phagocytic infiltrate. In addition, we observe accelerated decline of microglia/macrophages and enhanced generation of oligodendrocytes in aged mice when n-3 fatty acids are shuttled to the brain. Thus, n-3 fatty acids enhance lesion recovery and may, therefore, provide the basis for pro-regenerative medicines of demyelinating diseases in the central nervous system. Graphical abstract Highlights • Lipid and fatty acid abundance is specifically altered during de- and remyelination• Reduction of pro- and anti-inflammatory lipid mediators impairs lesion recovery• DHA supplementation fosters phagocyte decline and oligodendrocyte generation• n-3 fatty acid supplementation may be a strategy to promote remyelination Penkert et al. employ sequential proteomics and lipidomics to elucidate the role of lipid mediators in lesion recovery in a mouse model of focal, cerebral demyelination. Using genetic and pharmacologic interventions, they find n-3 fatty acid supplementation, specifically DHA, to enhance innate inflammation resolution and oligodendrocyte generation.

SUBMITTER: Penkert H 

PROVIDER: S-EPMC8567315 | biostudies-literature |

REPOSITORIES: biostudies-literature