Microglia clean up toxic lipids in multiple sclerosis

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frodo
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Microglia clean up toxic lipids in multiple sclerosis

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Microglia clean up toxic lipids in multiple sclerosis

https://www.nature.com/articles/s41593-021-00829-1

Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination and neurodegenerative processes, including axonal damage and, in the most aggressive cases, neuronal loss in the CNS. This debilitating disease is a leading cause of neurological disability in young adults, with a majority of cases diagnosed between the ages of 20–50. No causal genes have been identified for MS; however, genome wide association studies have identified over 200 variants and implicated cells of both the adaptive and innate immune system1.

The pathological hallmarks of MS are demyelinating lesions in the brain or spinal cord that are infiltrated with self-reactive adaptive immune cells2. The widely held view of MS disease progression is that autoimmune lymphocytes attack and destroy the myelin sheath, rendering oligodendrocytes and axons susceptible to death, which drives subsequent neurodegeneration, but it remains unclear whether myelin debris contribute to neurotoxicity and if so, what mechanisms are involved.

In this issue of Nature Neuroscience, Dong et al. show that oxidized phosphatidylcholines (OxPCs) are present exclusively in MS lesions, but not in adjacent normal white matter3. Prior to this work, OxPCs were reported in MS lesions4, but Dong et al. provide evidence that these lipid species are pathogenic. Indeed, they found a cell-type-specific response to OxPCs characterized by neuron and oligodendrocyte death and recruitment of microglia/macrophages to the site of lipid deposition (Fig. 1).

In cell culture, OxPCs, but not other non-oxidized phospholipids or oxidized cholesteryl esters, induced neuron and oligodendrocyte death, whereas astrocytes were unaffected. These findings translated in vivo, as oligodendrocytes were rapidly depleted following OxPC injection, and axonal degeneration was also observed. The mechanisms mediating susceptibility of neurons and oligodendrocytes and protection of astrocytes to OxPC-induced cell death were not investigated, but could be of interest for future studies.

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