Microglial autophagy–associated phagocytosis is essential for recovery from neuroinflammation
Sci. Immunol. 2020;5:eabb5077.
Rasmus Berglund, Andre Ortlieb Guerreiro-Cacais, Milena Z. Adzemovic, Manuel Zeitelhofer, Harald Lund, Ewoud Ewing, Sabrina Ruhrmann, Erik Nutma, Roham Parsa, Melanie Thessen-Hedreul, Sandra Amor, Robert A. Harris, Tomas Olsson and Maja Jagodic
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.Click here to jump original article page
2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science From Science Immunology 16 Oct 2020: Vol. 5, Issue 52, eabb5077. Reprinted with permission from AAAS.