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Characterizing microglial gene expression in a model of chronic-relapsing EAE

ABSTRACT: Multiple sclerosis (MS) is the most common inflammatory, demyelinating and neurodegenerative disease of the central nervous system in young adults. Chronic-relapsing experimental autoimmune encephalomyelitis (crEAE) in Biozzi ABH mice is an experimental model of MS. This crEAE model is characterized by an acute phase with severe neurological disability, followed by remission of disease, relapse of neurological disease and remission that eventually results in a chronic progressive phase that mimics the secondary progressive phase (SPEAE) of MS. In both MS and the SPEAE the role of microglia is poorly defined. We used the crEAE model to characterize microglia in the different phases of crEAE phases using morphometric and RNA sequencing analyses. At the initial, acute inflammation phase, microglia acquired a pro-inflammatory phenotype. At remission phase, expression of standard immune activation genes was decreased while expression of genes associated with lipid metabolism and wound healing was increased. Chronic phase microglia partially regain inflammatory gene sets and increase expression of genes associated with proliferation. Together, the data presented here indicates that microglia obtain different features at different stages of crEAE and a particularly mixed phenotype in the chronic stage. Understanding the properties of microglia that are present at the chronic phase of EAE may help understand the role of microglia in progressive neurological disease to better aid the development of therapies for secondary progressive MS.

ORGANISM(S): Mus musculus

PROVIDER: GSE194071 | GEO | 2022/11/15

REPOSITORIES: GEO

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Project description:Multiple Sclerosis (MS) is a leading cause of incurable progressive disability in young adults caused by inflammation in the central nervous system (CNS) that triggers demyelination, glial cell dysfunction and irreversible neuro-axonal damage1. While considerable progress has been made in treating early inflammatory relapsing-remitting MS, the mechanisms underpinning the progressive stage remain largely unknown. The capacity of microglia, the CNS-resident phagocytes, to clear tissue debris is essential for both maintaining and restoring CNS homeostasis2,3 and this capacity diminishes with age4-6. Age strongly associates with the risk of developing progressive MS7,8. Herein we demonstrate that the recovery from inflammation is dependent on the ability of microglia to clear tissue debris and that blocking this process leads to development of progressive disease in a murine model of MS. Microglia-specific deletion of the general autophagy regulator Atg7, but not the canonical macroautophagy protein Ulk1, led to increased intracellular accumulation of phagocytosed myelin. This further associated with the alteration of the microglial phenotype towards that previously described in other neurodegenerative diseases2,3,9. Moreover, Atg7 deficient microglia showed striking similarities with microglia from aged wild type mice, which also demonstrated accumulation of myelin debris and inability to recover from MS-like disease. In contrast, the induction of autophagy using the disaccharide Trehalose in aged mice led to functional myelin clearance and remission from MS-like disease. Our results demonstrate that a non-canonical form of autophagy in microglia is responsible for myelin clearance and that impairment of this pathway markedly changes microglial phenotype and prevents recovery from MS-like disease. Importantly, we show that using a disaccharide ubiquitously found in plant-derived foods to boost autophagy in cells in which this process is naturally diminished can be utilized for therapeutic purposes.Project was run on 4 lanes with a 10M sequencing depth

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Characterizing microglial gene expression in a model of chronic-relapsing EAE

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