Proteomic and lipidomic profiling of demyelinating lesions identifies fatty acids as modulators in inflammation resolution

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After demyelinating injury of the central nervous system, resolution of the mounting acute innate inflammation is crucial for the initiation of a regenerative response. To identify factors in lesion recovery after demyelination injury, we used a toxin-induced model, in which a single dose of lysolecithin is injected into the corpus callosum to induce a focal demyelinating lesion. Afterwards, we investigated the proteome of demyelinating lesions at different time points post injection (dpi) in a time resolved manner. Lesion sites were excised analyzed from different mice at 0 dpi, without lysolecithin injection, as well as lysolecithin treated mice at 3 dpi, 7 dpi, and 14 dpi. Overall, immune cell migration, especially infiltration of microglia and macrophages, as well as fatty acid metabolism are playing crucial roles for the immidiate response, repair and finally lesion recovery. Additionally, Using lipidomics and eicosanoidomics, we identified bioactive lipids in the resolution phase of inflammation with a marked induction of n-3 polyunsaturated fatty acids. Using fat-1 transgenic mice, which convert n-6 fatty acids to n-3 fatty acids, we found that reduction of the n-6/n-3 ratio facilitates inflammation resolution. In addition, we observed accelerated inflammation resolution and enhanced generation of oligodendrocytes in aged mice when n-3 fatty acids are shuttled to the brain. Thus, n-3 fatty acids and eicosanoids, their oxidized bioactive products, enhance lesion recovery and may therefore provide the basis for novel pro-regenerative medicines of demyelinating diseases in the central nervous system.