Excessive inflammation within the CNS is injurious, but an immune response is also required for regeneration. Macrophages and microglia adopt different properties depending upon their microenvironment, and exposure to interleukin-4 and -13 (IL4/IL13) has been used to elicit repair. Unexpectedly, while lipopolysaccharide (LPS)-exposed macrophages and microglia killed neural cells in culture, the addition of LPS to IL4/IL13-treated macrophages and microglia profoundly elevated IL10, repair metabolites, HBEGF trophic factor, antioxidants, and matrix-remodeling proteases. In C57BL/6 female mice the generation of M(LPS/IL4/IL13) macrophages required TLR4 and MyD88 signaling, downstream activation of PI3K/mTOR and MAP kinases, and convergence upon phospho-CREB, STAT6 and NFE2. Following mouse spinal cord demyelination, local LPS/IL4/IL13 deposition markedly increased lesional phagocytic macrophages/microglia, lactate and HBEGF, matrix remodeling, oligodendrogenesis and remyelination. Our data show that a promine...