Microglia necroptosis is necessary for the remyelination of central nervous system.

Lack of remyelination and microglial activation in the central nervous system (CNS) are common features of several neurodegenerative diseases (e.g. multiple sclerosis, amiotrophic lateral sclerosis, spinal cord injury). On the other end, effective regeneration of the axonal myelin sheath strongly depends on the capacity of CNS-resident microglia of undergoing a phenotypical transition during which pro-inflammatory markers (such as iNOS, TNF-alpha and CCL2) are downregulated and pro-resolving/pro-regenerative ones are expressed (Arg-1, CD206, IGF1). Lack of this conversion leads to impaired regeneration and remyelination, bu the causes that lead to this event are basically unknown. In this paper, Amy Lloyd and colleagues, investigated the molecular mechanisms that underlie the regeneration of the CNS lesions mediated by the functional transition of microglia and saw that, quite interestingly, remyelination depends on the necroptosis of pro-inflammatory microglia in the early moments of the lesion and on the consequent repopulation of the lesioned site of pro-regenerative microglial phenotypes.

The authors used a self-resolving/regenerating mouse model, which consists of a lysophosphatidyl choline (LPC) injection in the corpum callosum, and isolated perilesional microglia at different moments, during the process of remyelination, in order to analyze their immunophenotype. Quite interestingly, not only pro-inflammatory microglial cells die in the earlier days after the induction of the lesion, but this event seems to be necessary for the subsequent remyelination (driven by the repopulation of pro-regenerative microglia), in that inhibition of their programmed death impaired tissue regeneration. The authors also analyzed human lesions from multiple sclerosis patients, and observed that the lesions with higher remylinating power were the ones that exhibited higher microglial necroptosis markers.

Source: Nature Neuroscience

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