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Pro-inflammatory activation following demyelination is required for myelin clearance and oligodendrogenesis.

J Exp Med. 2020 May 4;217(5). pii: e20191390. doi: 10.1084/jem.20191390.

Authors/Editors: Cunha MI, Su M, Cantuti-Castelvetri L, Müller SA, Schifferer M, Djannatian M, Alexopoulos I, van der Meer F, Winkler A, van Ham TJ, Schmid B, Lichtenthaler SF, Stadelmann C, Simons M.
Publication Date: 2020



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.

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