Editors' ChoiceNEUROREGENERATION

Live and let die

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Science Translational Medicine  03 Jul 2019:
Vol. 11, Issue 499, eaay4741
DOI: 10.1126/scitranslmed.aay4741

Abstract

Death and replacement of microglia is required for effective remyelination of damaged axons.

The central nervous system has the capacity to newly wrap axons in insulating myelin after injury (remyelinate); failure to do so underlies the axonal degeneration observed in several diseases, including multiple sclerosis. A transition from pro-inflammatory to pro-regenerative microglia orchestrates remyelination by promoting the differentiation of myelinating oligodendrocytes, although the mechanisms regulating this switch remain largely unknown.

A new study by Lloyd and colleagues examined microglial activity during remyelination. They used a remyelination model with stereotypical microglia transition timing, where axon bundles in the brain are lesioned following injection of a myelin toxin in young adult mice. RNA sequencing experiments performed in purified microglia at the peak pro-inflammatory response 3 days post-injection revealed an enrichment in the expression of genes in death-associated pathways, in comparison with microglia isolated at the peak pro-regenerative response a week later. Consistent with this, microglia density decreased from 3 to 7 days post-injection, with concomitant increase in microglia expressing markers of death, and lesions repopulated with new microglia by 10 days post-injection. The authors determined the microglia died by necroptosis. The necroptosis inhibitor necrostatin-1 was able to preserve pro-inflammatory microglia numbers, yet it also interfered with the remyelination process. When examining different types of multiple sclerosis lesions, necroptotic microglia were most abundantly detected in the lesions actively undergoing remyelination, as opposed to inactive or fully remyelinated lesions, suggesting relevance of these findings to human disease. Genetic labeling of neural progenitor cells before demyelination indicated that the new microglia observed at 10 days post-injection most likely arose from the survivors of the necroptotic surge. Gene expression analysis and immunolabeling of these new microglia pointed toward type-1 interferon (IFN) signaling playing a role in regulating them during remyelination. Accordingly, an antibody neutralizing an IFN receptor subunit prevented microglia repopulation, which also impaired remyelination.

The need for a purge in pro-inflammatory microglia to allow pro-regenerative microglia rebirth and proper remyelination is thought-provoking. Follow up studies could address many intriguing questions, such as how dead microglia are removed, why a small number circumvents death and, importantly, how the process goes awry in demyelinating diseases.

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