Harnessing the Benefits of Neuroinflammation: Generation of Macrophages/Microglia with Prominent Remyelinating Properties

J Neurosci. 2021 Apr 14;41(15):3366-3385. doi: 10.1523/JNEUROSCI.1948-20.2021. Epub 2021 Mar 12.


Excessive inflammation within the CNS is injurious, but an immune response is also required for regeneration. Macrophages and microglia adopt different properties depending on their microenvironment, and exposure to IL4 and IL13 has been used to elicit repair. Unexpectedly, while 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, heparin binding epidermal growth factor 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 phosphatidylinositol-3 kinase/mTOR and MAP kinases, and convergence on phospho-CREB, STAT6, and NFE2. Following mouse spinal cord demyelination, local LPS/IL4/IL13 deposition markedly increased lesional phagocytic macrophages/microglia, lactate and heparin binding epidermal growth factor, matrix remodeling, oligodendrogenesis, and remyelination. Our data show that a prominent reparative state of macrophages/microglia is generated by the unexpected integration of pro- and anti-inflammatory activation cues. The results have translational potential, as the LPS/IL4/IL13 mixture could be locally applied to a focal CNS injury to enhance neural regeneration and recovery.SIGNIFICANCE STATEMENT The combination of LPS and regulatory IL4 and IL13 signaling in macrophages and microglia produces a previously unknown and particularly reparative phenotype devoid of pro-inflammatory neurotoxic features. The local administration of LPS/IL4/IL13 into spinal cord lesion elicits profound oligodendrogenesis and remyelination. The careful use of LPS and IL4/IL13 mixture could harness the known benefits of neuroinflammation to enable repair in neurologic insults.

Keywords: macrophages; microglia; neuroinflammation; oligodendrocyte; remyelination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Coculture Techniques / methods
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Female
  • Inflammation
  • Interleukin-13 / pharmacology
  • Interleukin-4 / pharmacology
  • Lipopolysaccharides / toxicity
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Microglia / drug effects
  • Microglia / metabolism*
  • Myelin Sheath / metabolism*
  • Myeloid Differentiation Factor 88 / metabolism
  • NF-E2 Transcription Factor, p45 Subunit / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • STAT6 Transcription Factor / metabolism
  • Signal Transduction*
  • Spinal Cord / metabolism*
  • Spinal Cord / pathology
  • Spinal Cord / physiology
  • Spinal Cord Regeneration*
  • TOR Serine-Threonine Kinases / metabolism
  • Toll-Like Receptor 4 / metabolism


  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Interleukin-13
  • Lipopolysaccharides
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • NF-E2 Transcription Factor, p45 Subunit
  • Nfe2 protein, mouse
  • STAT6 Transcription Factor
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Interleukin-4
  • TOR Serine-Threonine Kinases

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