IL-33-PU.1 Transcriptome Reprogramming Drives Functional State Transition and Clearance Activity of Microglia in Alzheimer's Disease.
Cell Rep
; 31(3): 107530, 2020 04 21.
Article
em En
| MEDLINE
| ID: mdl-32320664
ABSTRACT
Impairment of microglial clearance activity contributes to beta-amyloid (Aß) pathology in Alzheimer's disease (AD). While the transcriptome profile of microglia directs microglial functions, how the microglial transcriptome can be regulated to alleviate AD pathology is largely unknown. Here, we show that injection of interleukin (IL)-33 in an AD transgenic mouse model ameliorates Aß pathology by reprogramming microglial epigenetic and transcriptomic profiles to induce a microglial subpopulation with enhanced phagocytic activity. These IL-33-responsive microglia (IL-33RMs) express a distinct transcriptome signature that is highlighted by increased major histocompatibility complex class II genes and restored homeostatic signature genes. IL-33-induced remodeling of chromatin accessibility and PU.1 transcription factor binding at the signature genes of IL-33RM control their transcriptome reprogramming. Specifically, disrupting PU.1-DNA interaction abolishes the microglial state transition and Aß clearance that is induced by IL-33. Thus, we define a PU.1-dependent transcriptional pathway that drives the IL-33-induced functional state transition of microglia, resulting in enhanced Aß clearance.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transativadores
/
Proteínas Proto-Oncogênicas
/
Microglia
/
Doença de Alzheimer
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Interleucina-33
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
/
Humans
/
Male
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2020
Tipo de documento:
Article