Research ArticleNEUROIMMUNOLOGY

Microglial autophagy–associated phagocytosis is essential for recovery from neuroinflammation

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Science Immunology  16 Oct 2020:
Vol. 5, Issue 52, eabb5077
DOI: 10.1126/sciimmunol.abb5077

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Microglia Matter

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, and microglial activation is linked to its progression. Berglund et al. show that microglia carry out a noncanonical form of autophagy that targets degradation and clearance of myelin. Deletion of the autophagy regulator Atg7, but not the canonical macroautophagy protein Ulk1, was associated with greater accumulation of phagocytosed myelin and lack of recovery from MS-like disease in mice. Microglia from aged wild-type mice with MS-like disease had functional and phenotypic similarities to Atg7-deficient microglia, but treatment of aged mice with trehalose promoted myelin clearance and disease remission. These results suggest that a noncanonical form of autophagy in microglia is critical to myelin degradation and clearance, thus providing insight into microglia function during MS.

Abstract

Multiple sclerosis (MS) is a leading cause of incurable progressive disability in young adults caused by inflammation and neurodegeneration in the central nervous system (CNS). The capacity of microglia to clear tissue debris is essential for maintaining and restoring CNS homeostasis. This capacity diminishes with age, and age strongly associates with MS disease progression, although the underlying mechanisms are still largely elusive. Here, we demonstrate that the recovery from CNS inflammation in a murine model of MS is dependent on the ability of microglia to clear tissue debris. Microglia-specific deletion of the autophagy regulator Atg7, but not the canonical macroautophagy protein Ulk1, led to increased intracellular accumulation of phagocytosed myelin and progressive MS-like disease. This impairment correlated with a microglial phenotype previously associated with neurodegenerative pathologies. Moreover, Atg7-deficient microglia showed notable transcriptional and functional similarities to microglia from aged wild-type mice that were also unable to clear myelin and recover from disease. In contrast, induction of autophagy in aged mice using the disaccharide trehalose found in plants and fungi led to functional myelin clearance and disease remission. Our results demonstrate that a noncanonical form of autophagy in microglia is responsible for myelin degradation and clearance leading to recovery from MS-like disease and that boosting this process has a therapeutic potential for age-related neuroinflammatory conditions.

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