Dataset Information

Pro-inflammatory activity following demyelinating injury is required for phagocytic function and oligodendrocyte formation

ABSTRACT: Remyelination can occur naturally in demyelinating lesions, but often fails in human demyelinating diseases such as multiple sclerosis (MS). The function of the innate immune system is essential for the regenerative response, 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 nuclear factor κB (NF-κB) dependent activation occurs in phagocytes rapidly after myelin injury. We found that the pro-inflammatory response depends on myeloid differentiation primary response 88 (MyD88), the canonical adaptor for inflammatory signaling pathways downstream of toll-like receptors (TLRs). MyD88-deficient mice and zebrafish were impaired not only in the degradation of myelin debris, but also in initiating the generation of new oligodendrocytes for myelin repair. We identified reduced generation of tumor necrosis factor-α (TNF-α) in lesions of MyD88-deficient animals, a pro-inflammatory molecule that was able to induce the generation of new oligodendrocytes. Our study shows that pro-inflammatory phagocytic signaling is an evolutionary conserved mechanism necessary for degrading myelin debris, essential for inflammation resolution, and for initiating the secretion of pro-inflammatory myelin repair molecules.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Microglial Cell

SUBMITTER: Stephan Mueller

LAB HEAD: Stefan Lichtenthaler

PROVIDER: PXD014625 | Pride | 2020-02-17

REPOSITORIES: Pride

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Publications

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

Cunha Maria Inês MI Su Minhui M Cantuti-Castelvetri Ludovico L Müller Stephan A SA Schifferer Martina M Djannatian Minou M Alexopoulos Ioannis I van der Meer Franziska F Winkler Anne A van Ham Tjakko J TJ Schmid Bettina B Lichtenthaler Stefan F SF Stadelmann Christine C Simons Mikael M

The Journal of experimental medicine 20200501 5

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 th ...[more]

PMID: 32078678

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Project description:In multiple sclerosis (MS) and experimental models of demyelination, myelin repair is mostly achieved by oligodendrocyte precursor cells (OPCs). To gain insight into the biological specificity of these adult precursors, in the perspective to better understand why remyelination often fails in MS, we performed a micro-array analysis on purified populations of murine OPCs and oligodendrocytes. We demonstrated that, in a control environment, M-bM-^@M-^\quiescentM-bM-^@M-^] adult OPCs are more mature than neonatal OPCs, with a mRNA profile closer to oligodendrocytes. However, when demyelination occurs, adult OPCs revert to an immature gene expression profile, acquiring higher migration and faster differentiation capacities. Among the many genes differentially regulated by these M-bM-^@M-^\activatedM-bM-^@M-^] adult OPCs, genes of the innate immune response, IL1M-NM-2 and CCL2 were strongly upregulated after demyelination, with increased protein expression in experimental demyelinating lesions and within MS plaques. We first showed in vitro that both IL1M-NM-2 and CCL2 M-bM-^@M-^\accountM-bM-^@M-^] for increased migration capacities of adult OPCs, an effect that is suppressed by corresponding receptor blockade. Focusing on Ccl2, we then demonstrated that lentiviral over-expression of Ccl2 increases motility of M-bM-^@M-^\quiescentM-bM-^@M-^] adult OPCs, which become as mobile as M-bM-^@M-^\activatedM-bM-^@M-^] adult OPCs. This in vitro gain of function was further confirmed in vivo, by showing an increased migration of grafted CG4 oligodendroglial cells over-expressing-Ccl2. These results, demonstrating that M-bM-^@M-^\activatedM-bM-^@M-^] adult OPCs upregulate immune cues favouring their migration, open new perspective of demyelination-induced immune-glial interactions, which might influence both oligodendroglial and inflammatory cells, therefore play a key role in lesion fate in multiple sclerosis. In this study, we loaded purified population of progenitors of oligodendrocytes (OPCs) (from neonatal, 2-month-old, 2-month-old and cuprizone-treated brains) and of mature oligodendrocytes (OLs) (2-month-old brains) and compared their gene expression. We compared gene expression of neonatal OPCs, adult OPCs, adult OLs and adult OPCs from control conditions and from demyelinating conditions, using 3 to 4 independant replicates in each group.

Dataset Information

Pro-inflammatory activity following demyelinating injury is required for phagocytic function and oligodendrocyte formation

Publications

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

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