Generation of macrophages that are profoundly pro-remyelinating through unexpected activation cues

Excessive inflammation within the central nervous system is injurious, but an immune response is also required for its repair. Macrophages are versatile cells that adopt different properties depending upon their microenvironment. Exposing macrophages to interleukin-4 and -13 (IL4/IL13) has incurred interest for their reparative properties. Unexpectedly, while macrophages exposed to the classic pro-inflammatory signals (interferon-γ/lipopolysaccharide, IFN/LPS) killed neurons and oligodendrocytes in culture, the addition of LPS to IL4/IL13-treated macrophages profoundly elevated IL10, repair metabolites (lactate, ornithine), glucose metabolism and the oligodendrocyte-trophic heparin-binding epidermal growth factor (HBEGF); cells did not display pro-inflammatory or neurotoxic features. In mice with spinal cord demyelination, locally-applied IL4/IL13 was insufficient to alter responses beyond controls; remarkably, the LPS/IL4/IL13-treated animals significantly increased lesional phagocytic macrophages/microglia, lactate and HBEGF levels, oligodendrogenesis and remyelination. We report a remarkably reparative state of macrophages that is unexpectedly generated by the integration of pro- (LPS) and anti- (IL4/IL13) inflammatory activation cues.