ZFIN ID: ZDB-PUB-200222-12
Pro-inflammatory activation following demyelination is required for myelin clearance and oligodendrogenesis
Cunha, M.I., Su, M., Cantuti-Castelvetri, L., Müller, S.A., Schifferer, M., Djannatian, M., Alexopoulos, I., van der Meer, F., Winkler, A., van Ham, T.J., Schmid, B., Lichtenthaler, S.F., Stadelmann, C., Simons, M.
Date: 2020
Source: The Journal of experimental medicine   217(5): (Journal)
Registered Authors: Schmid, Bettina, van Ham, Tjakko
Keywords: none
MeSH Terms:
  • Animals
  • Axons/drug effects
  • Axons/pathology
  • Cells, Cultured
  • Demyelinating Diseases/pathology*
  • Disease Models, Animal
  • Inflammation/pathology*
  • Larva/drug effects
  • Lysophosphatidylcholines/metabolism
  • Mice
  • Microglia/drug effects
  • Microglia/metabolism
  • Mutation/genetics
  • Myelin Sheath/drug effects
  • Myelin Sheath/metabolism*
  • Myelin Sheath/pathology
  • Myeloid Differentiation Factor 88/metabolism
  • Oligodendroglia/drug effects
  • Oligodendroglia/metabolism
  • Oligodendroglia/pathology*
  • Phagocytes/drug effects
  • Phagocytes/pathology
  • Phagosomes/drug effects
  • Phagosomes/metabolism
  • Proteome/metabolism
  • Remyelination/drug effects
  • Spinal Cord/pathology
  • Tumor Necrosis Factor-alpha/pharmacology
  • Zebrafish
PubMed: 32078678 Full text @ J. Exp. Med.
Remyelination requires innate immune system function, but how exactly microglia and macrophages clear myelin debris after injury and tailor a specific regenerative response is unclear. Here, we asked whether pro-inflammatory microglial/macrophage activation is required for this process. We established a novel toxin-based spinal cord model of de- and remyelination in zebrafish and showed that pro-inflammatory NF-κB-dependent activation in phagocytes occurs rapidly after myelin injury. We found that the pro-inflammatory response depends on myeloid differentiation primary response 88 (MyD88). MyD88-deficient mice and zebrafish were not only impaired in the degradation of myelin debris, but also in initiating the generation of new oligodendrocytes for myelin repair. We identified reduced generation of TNF-α in lesions of MyD88-deficient animals, a pro-inflammatory molecule that was able to induce the generation of new premyelinating oligodendrocytes. Our study shows that pro-inflammatory phagocytic signaling is required for myelin debris degradation, for inflammation resolution, and for initiating the generation of new oligodendrocytes.